Synthesis of amines and intermediates for the synthesis thereof

ABSTRACT

The invention relates in a first embodiment to a method for the manufacture of esters of the formula I, 
                         
or especially of amides of the formula II,
 
                         
wherein the symbols have the meanings given in the specification, as well as other intermediates and compounds useful in the synthesis of tryptamines and other substances mentioned in the title. The synthesis methods and intermediates are useful in the synthesis of pharmaceuticals.

This application is a divisional of U.S. patent application Ser. No.12/631,894, filed on Dec. 7, 2009, now issued as U.S. Pat. No.7,968,730, which is a divisional of U.S. patent application Ser. No.10/539,151, filed on Jun. 16, 2005, now issued as U.S. Pat. No.7,645,886, which is a 371 of international app. No. PCT/EP2003/50992,filed Dec. 12, 2003, which claims priority to EP 02406128.5, filed Dec.20, 2002, all of which are herein incorporated by reference.

SUMMARY OF THE INVENTION

The present invention provides a novel process (=method) for themanufacture of derivatives, especially precursors, of tryptamine,horsfiline or coerulescine, novel partial reactions and novelintermediates. The derivatives or precursors of tryptamine, horsfilineand coerulescine are useful e.g. in the pharmaceutical area.

BACKGROUND OF THE INVENTION

Derivatives of tryptamine 1

have been synthesized from substituted anilines. Some pertinent anilinesare prepared from 4-nitro benzyl chloride (precursors for anti migrainepharmaceuticals such as Sumatriptan 2 see: DE 3,320,521, U.S. Pat. No.4,816,470, Almotriptan 3 see: Res. Disci. 1998, 412, 1088, Rizatriptan 4see: EP 0497512A2) or Zolmitriptan 5 from 4-nitro phenyl alanine see: WO91/18897.

A variety of strategies have been disclosed for the conversion of theanilines 2, 3, 4 or 5 into the related tryptamine derivative 1. In themost common approach (scheme 2), the aniline A is converted into thecorresponding phenyl hydrazine B. This is then reacted with a4-halogeno-butyraldehyde derivative C (e.g. the dimethyl acetal (see:U.S. Pat. No. 4,816,470) or the sodium sulfite addition product (see: EP462 837 A2 or U.S. Pat. No. 5,103,020)) or with a derivative of 4-aminobutyraldehyde to give tryptamine D. Methylation of the amine of Dprovides the corresponding drug H. Alternatively, aniline A may beconverted into indole E. A variety of pathways for the subsequentconversion of E into H is disclosed in U.S. Pat. No. 5,037,845.

One important problem regarding these approaches is the conversion ofaniline A into phenyl hydrazine B. The reduction of the diazonium saltderived from A has been performed using tin(II)chloride in a three tofive-fold excess. A range of environmentally more suitable reducingagents has been identified, and is claimed in patent application WO01/34561.

For a detailed account of problems in the preparation of the phenylhydrazine that is derived from 2 and its transformation into Sumatriptansee: Heterocycles 1998, 48, 1139. Similar problems can be expected forphenyl hydrazines that are derived from anilines 3, 4, and 5. Thus, theuse of α-keto-δ-valerolactone as the carbonyl component for theFischer-cyclisation has been suggested as an alternative, see: SK280586B (Applicant: QUMICA SINT S A (ES); VITA INVEST, Publication date2000-4-10).

A quite different approach to synthesize Sumatriptan also requiresaniline 2, but the preparation of the phenyl hydrazine is avoided, see:Heterocycles 2000, 53, 665. Here, the diazonium salt from 2 is reactedwith a β-ketocarboxylic acid ester, and the formed hydrazone is cyclisedto the indole 2-carboxylic acid which is decarboxylated to a derivativeof 1.

A major problem of the Fischer indolisation is that frequently only lowyields of the indole are obtained due to the lack of stability of theproduct under the rather strongly acidic reaction conditions. Moreover,a problem of the Grandberg indolisation is that the reductivedi-methylation of the primarily formed tryptamine in an alternative wayis prone to low yields as side reactions such as formation of carbazolesand methylation of the indole nitrogen can take place. A solution toboth of these problems is provided by using a derivative ofN,N-dimethyl-4-aminobutyraldehyde in a modified Fischer indolisationprotocol, see: J. Org. Chem. 1994, 59, 3738.

In all synthesis variants for derivatives of tryptamine 1 presented sofar, the nature of the final product is determined early at the anilinestage. The final product is then obtained through the identical steps ofhydrazine synthesis and Fischer indole cyclisation with all thedescribed limitations. The present invention describes a route to latecommon intermediates for the synthesis of derivatives of tryptamine suchas 1 which avoids both the synthesis of phenyl hydrazones and variationsof the Fischer indolisation.

The reaction of isatin (or a derivative) with malonic acid in aceticacid, either in the presence or absence of sodium acetate, furnishes thequinolone carboxylic acid 6 instead of the expected product 7, see J.Chem. Soc. 1926, 2902 and Chem. Ber. 1914, 47, 354.

However, compounds such as 7 are known, and have been prepared forexample by reacting isatin or a derivative of it with the Reformatzkyreagent of a derivative of bromo acetic acid, see Chem. Ber. 1962, 95,1138 or Tetrahedron 1967, 23, 901 or with a 15-fold excess of thelithium enolate of tert-butyl acetate, see J. Org. Chem. 1988, 53, 2844.Derivatives of 7 also have been prepared by the condensation of anisatin with methyl acetimidate and subsequent hydrolysis, see LiebigsAnn. Chem. 1967, 701, 139 or by the oxidation of the enolate of a3-methoxycarbonylmethyl-2-oxo-2,3-dihydro-1H-indol-5-yl derivative withDavies reagent, see Heterocycles 1998, 47, 49.

Analogues of 7 have been obtained when a derivative of isatin wherein R₂is a substitutent hydrogen or ethyl was reacted with malonic acid inpyridine (see Garden et al., Tetrahedron 58, 8399-8412 (2002)). In thiscase the pyridinium salt 8 was obtained, from which the correspondingacid 9 was obtained simply by acidification with hydrochloric acid.

9 was then transformed into the corresponding ester in the presence ofmethanol and the ester then reduced with sodium borohydride to yield thecorresponding tryptophol 9a:

However, it was observed that when R₂ is hydrogen (non-N-alkylatedisatin) the corresponding esterification does not work. Therefore analternative procedure employing the potassium salt of the mono-ethylmalonyl ester with 7-ethylisation in a mixture of pyridine, acetic acidand ethanol under reflux was used which gave the corresponding esterthat could then be reduced.

GENERAL DESCRIPTION OF THE INVENTION

It has now been found surprisingly that when a compound such as 8 isreacted with an appropriate nitrogen base, especially a tertiary amine,such as triethyl amine (given in scheme 7 as an example only), itbecomes sufficiently nucleophilic to react either with an activecarbonic ester such as 10 (wherein R′ is, for example, lower alkyl) oran active amide such as chloro amido carbonic acid derivative 12(wherein R₃ and R₄ are unsubstituted or substituted alkyl or togetherform a lower alkylene bridge) to give an ester such as 11 or anN,N-disubstituted alkylamide derivative such as 13 of 9. Veryadvantageously and surprisingly, the condensation step can convenientlybe combined with the derivatisation step, which allows to obtain esters11 or especially amides 13 of 9 in a one pot reaction. In this contexttriethylamine cannot be used for the addition reaction of malonic acidto isatin. (In formulae 11 and 13 and their precursors in brackets, R1represents one or more substitutents and R2 a nitrogen substituent).

Compounds such as 9, 11 or 13 are also valuable starting materials forfurther unprecedented conversion reactions into various derivatives orprecursors of tryptamine 1 which are described in more detail below.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates in a first embodiment to a method for themanufacture of esters of the formula I,

wherein n is a number from 0 to 4,each R₁ is, independently of the other substituents R₁, unsubstituted orsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heterocyclyl, alkylsulfonyl, alkyl sulfonyl, sulfonyl alkyl,unsubstituted, N-mono- or N,N-disubstituted or unsubstitutedaminosulfonyl alkyl, hydroxy, mercapto, nitro, halogen, cyano,carboxamido, N-mono- or N,N-disubstituted carboxamido, unsubstituted orsubstituted alkoxycarbonyl, unsubstituted or substituted alkoxy, formylor other alkanoyl, unsubstituted or substituted alkenyl or unsubstitutedor substituted alkynyl;R2 is hydrogen or unsubstituted or substituted alkyl, unsubstituted orsubstituted alkoxycarbonyl, unsubstituted or substituted arylsulfonyl,unsubstituted or substituted alkylsulfonyl, unsubstituted or substitutedaryl, carbamoyl or N-mono- or N,N-disubstituted carbamoyl, silylsubstituted by three moieties independently selected from unsubstitutedor substituted alkyl and substituted or unsubstituted aryl, or acyl, andR′ is unsubstituted or substituted alkyl,or especially of amides of the formula II,

wherein n, R₁ and R₂ are as defined under formula I and R₃ and R₄ are,independently of each other, unsubstituted or substituted alkyl ortogether form an unsubstituted or substituted alkylene bridge (thusforming a ring with the binding nitrogen) or an alkylene bridge to whicha phenyl or a C₃-C₈-cycloalkyl ring is condensed at two vicinal carbonatoms of the alkylene bridgewhere a starting material of the formula III,

wherein n, R₁ and R₂ have the meanings given under formula I and NB is atertiary nitrogen base where the nitrogen is not part of a ring,is reacted

-   -   (a) for the synthesis of an ester of the formula I with an        active carbonic ester of the formula IV,

wherein X is halogen and R′ is as defined under formula I, to give thecorresponding ester of the formula I, or

-   -   (b) for the synthesis of an amide of the formula II with an        active amido carbonic acid derivative of the formula V,

wherein X is halogen and R3 and R4 are as defined under formula II, togive the corresponding compound of the formula II.

Further to the above definitions, R₁ may also be unsubstituted orsubstituted cycloalkyl, alkanoyloxy, carboxhydrazido, N-mono- orN,N-disubstituted or unsubstituted amino, unsubstituted or substitutedhydrazino, or a residue of a boronic acid or an ester thereof. Such aboronic acid residue preferably conforms to the formula

wherein R₃₀ and R₃₁ independently are hydrogen or a radical of analcohol, e.g. lower alkyl, or together are C₂-C₈alkylene; preferred R₃₀and R₃₁ independently are hydrogen or a residue of a sterically hinderedalcohol such as isopropanol or pinakol.

In an especially preferred method, NB is a tri-lower alkylamine,especially triethylamine. The compound of the formula III is preferablyobtained by reaction of an isatine derivative of the formula VI,

wherein n, R₁ and R₂ have the meanings given under formula I, withmalonic acid in the presence of a pyridine, especially pyridine and/orone or more picolines, in the absence or presence of a N,N-di-(lowerAA-lower alkanoylamide, a lower alkanol, e.g. methanol or ethanol, or adi-lower alkylsulfoxide, e.g. dimethylsulfoxide, especially N,N-dimethylformamide, advantageously in the presence of ethyl acetate as acosolvens, followed by conversion into the salt of the base NB given informula IIIby conversion of the resulting product of the formula III*,

wherein n, R₁ and R₂ have the meanings given under formula I and HPyr⁺is the respective cation resulting from a pyridine as mentioned above.

Preferably, the reaction of the compound of the formula VI with malonicacid in the presence of a pyridine and optionally a co-solvent asdefined above, the subsequent conversion into the salt of the formulaIII with the base NB and reaction a) or b) above take place in the samereaction vessel (one pot synthesis).

The products of the formulae I or II can then be subjected to a numberof novel, unprecedented reactions that yield various products useful inthe synthesis of known or novel tryptamine derivatives with e.g.pharmacological useful properties.

In a first novel reaction, an amide of the formula II wherein n is zeroand thus R₁ is absent is converted to a compound of the formula VII,

wherein Ac is acetyl and R2, R3 and R4 have the meanings indicated forcompounds of the formula II with the proviso that in the compound of theformula II and of the formula VII, R2 is other than hydrogen, preferablyunsubstituted or substituted alkyl;by the reaction with formaldehyde or a precursor thereof in the presenceof acetic acid, and preferably an acidic catalyst, thus yielding a newtryptamine precursor.

In a further embodiment of the invention, the compound of the formulaVII is then transformed into the corresponding free alcohol of theformula VIII,

wherein R2, R3 and R4 are as defined under formula VII, another novelclass of tryptamine precursors. This conversion is preferably effectedby hydrolysis or transesterification.

In another embodiment of the invention, the alcohol of the formula VIIIis then

reacted with an oxidising agent to give the corresponding compound ofthe formula IX (a compound of the formula II wherein R₁ is formyl inpara position to the oxindole ring nitrogen)

-   -   wherein R2, R3 and R4 have the meanings given under formula VII,        again a novel intermediate in the synthesis of tryptanes.        Preferred oxidising agent is MnO₂.

In another embodiment of the invention, a compound of the formula IIwherein R2 has one of the meanings given above other than hydrogen isreacted with a dehydrating agent to give a compound of the formula Xa,

wherein n, R₁ and R2 are as defined under formula I and R3 and R4 are,independently of each other, unsubstituted or substituted alkyl,especially lower alkyl or phenyl lower alkyl, or together form anunsubstituted or substituted alkylene bridge, especially anunsubstituted or lower alkyl substituted lower alkylene bridge (thusforming a ring with the binding nitrogen).

In still another embodiment of the invention, the compound of theformula Xa is then reduced in the presence of a reductant to a compoundof the formula Xb,

wherein n, R₁, R2, R3 and R4 are as defined for a compound of theformula II.

In an alternative embodiment of the invention, a compound of the formulaXb as just described is obtained by hydrogenation of the benzylic3-hydroxy group in a compound of the formula II as just defined.

A compound of the formula Xb, e.g. as obtained in the above reactions,can surprisingly be converted to a Spiro oxindole of the formula XI byreaction with formaldehyde or a precursor thereof (e.g.paraformaldehyde):

Following the method of the invention, these compounds are readilyaccessible; they are useful as precursors for horsfiline or coerulescineor derivatives thereof (J. Org. Chem. 66, 8447, 2001, or Org. Lett. 3,4193, 2001).

In the novel compounds of the present invention and in the compoundsused and prepared in the process steps of the present invention(including educt compounds, e.g. of the formula II as described below),the substitutents and symbols, as far as present in the compounds of theformulae I to V, may have the following meanings:

n is an integer from 0 to 3, preferably from 0 to 2;

each R₁ is, independently of the other substituents R₁, lower alkyl,lower alkyl substituted by up to three moieties selected fromN,N-di-lower alkylamino, N-phenyl-lower alkylamino, N,N-bis(phenyl-loweralkyl)-amino, and halo-lower alkyl, e.g. trifluoromethyl),C₃-C₁₀-cycloalkyl, lower alkoxy, for example methoxy, aryl-lower alkoxy,e.g. phenyl-lower alkoxy, lower alkanoyloxy, N,N-di-lower alkylamino,N-phenyl-lower alkylamino, N,N-bis(phenyl-lower alkyl)-amino, di-loweralkylamino, unsubstituted or lower alkyl substituted and/or mono- ordi-oxosubstituted heterocyclylenyl or heterocyclyl, e.g.imidazolidin-2,4-dionenyl or imidazolidin-2,4-dionyl; unsubstituted orsubstituted aryl, unsubstituted or substituted heterocyclyl,alkylsulfonyl, sulfonyl alkyl, unsubstituted, N-mono- orN,N-disubstituted or unsubstituted aminosulfonyl alkyl, hydroxy,mercapto, nitro, halogen, cyano, carboxamido, N-mono- orN,N-disubstituted carboxamido, unsubstituted or substitutedalkoxycarbonyl, unsubstituted or substituted alkoxy, formyl or otheralkanoyl, unsubstituted or substituted alkenyl or unsubstituted orsubstituted alkynyl; unsubstituted or substituted aryl selected fromphenyl, naphthyl, indenyl, azulenyl and anthryl, preferablyunsubstituted or substituted by one or up to three moietiesindependently selected from those mentioned above as substituents forsubstituted alkyl;unsubstituted or substituted heterocyclyl selected from the groupconsisting of unsubstituted or oxo- and/or lower alkyl-substitutedimidazolidinyl, thienyl, oxazolidonyl or thienyl, such asimidazolidin-2,4-dionyl thienyl, 5H-oxazol-2-on-4-yl,2-methyl-4H-oxazol-4-on-5-diyl, pyrrolidinyl, such as pyrrolidin-1-yl,and triazolyl, such as 1,2,4-triazolyl;lower alkylsulfonyl; sulfonyl-lower alkyl; unsubstituted, N-mono- orN,N-di-lower alkyl substituted aminosulfonyl alkyl; hydroxy; mercapto;nitro; halogen; cyano; carboxamido; N-mono- or N,N-disubstitutedcarboxamido, wherein the substitutents are independently selected fromlower alkyl and phenyl-lower alkyl; unsubstituted or substitutedalkoxycarbonyl where the substituents are independently selected fromlower alkyl and phenyl-lower alkyl; unsubstituted or substituted alkoxywherein the substitutents are independently selected from lower alkyl orphenyl-lower alkyl; formyl or other lower alkanoyl; unsubstituted orlower-alkyl substituted lower alkenyl; or unsubstituted or phenyl-loweralkoxy-substituted lower alkynyl;R2 is hydrogen or unsubstituted or substituted alkyl with substituentsas defined for substituted lower alkyl R1, preferably phenyl-lower alkylor lower alkyl; unsubstituted or substituted lower alkoxycarbonylwherein the substituents are independently selected from lower alkyl andphenyl-lower alkyl; unsubstituted or substituted arylsulfonyl,unsubstituted or substituted alkylsulfonyl, especially loweralkyl-phenylsulfonyl or lower alkylsulfonyl; unsubstituted orsubstituted aryl wherein aryl and the substitutents are defined as underR1, preferably phenyl; carbamoyl or N-mono- or N,N-disubstitutedcarbamoyl as defined above for R2; silyl substituted by three moietiesindependently selected from unsubstituted or substituted lower alkyl asdefined for unsubstituted or substituted lower alkyl R1 and fromsubstituted or unsubstituted aryl as defined above for R1, or acylselected from lower alkoxycarbonyl, unsubstituted or substitutedaryloxycarbonyl or unsubstituted or substituted aryl-loweralkoxycarbonyl, each with unsubstituted or substituted aryl as definedabove for R1, or preferably aryl-carbonyl, aryl-lower alkylcarbonyl or(unsubstituted or substituted lower alkyl)-carbonyl wherein aryl, alkyland the substituents if present are preferably as defined above;especially lower alkanoyl, andR′ is unsubstituted or substituted alkyl;and in formula II R3 and R4 is lower alkyl or R3 and R4 together form alower alkylene bridge.

In the above compounds I to XI, each R₁ preferably is, where present,independently of the other substituents R₁,

lower alkyl;

lower alkyl substituted by up to three moieties selected fromN,N-di-lower alkylamino, N-phenyl-lower alkylamino, N,N-bis(phenyl-loweralkyl)-amino, N,N-di-lower acylamino, N-lower acylamino, alkylatedand/or acylated hydrazino of the formula R₂₀R₂₁N—N(R₂₂)— wherein R₂₀ isalkyl or acyl or substituted alkyl (e.g. benzyl) and R₂₁ is hydrogen orR₂₀ and R₂₂ is hydrogen or acyl;halo-lower alkyl (e.g. trifluoromethyl);C₃-C₁₀-cycloalkyl;lower alkoxy, for example methoxy;aryl-lower alkoxy, e.g. phenyl-lower alkoxy;lower alkanoyloxy;N,N-di-lower alkylamino;N-phenyl-lower alkylamino, N,N-bis(phenyl-lower alkyl)-amino,N′-phenyl-lower alkylhydrazino, N′,N′-bis(phenyl-lower alkyl)-hydrazino,each of which contains phenyl unsubstituted or substituted, preferablyunsubstituted;N′,N′-di-lower alkylhydrazino;unsubstituted or substituted aryl;unsubstituted or substituted heterocyclyl; unsubstituted or lower alkylsubstituted and/or mono- or di-oxosubstituted heterocyclenyl orheterocyclyl, e.g. imidazolidin-2,4-dionenyl or imidazolidin-2,4-dionylor thienyl;alkylsulfonyl;sulfonyl alkyl such as lower alkylsulfonylmethyl;unsubstituted, N-mono- or N,N-disubstituted aminosulfonyl alkyl such aspyrrolidin-1-yl-sulfonylmethyl, di-lower alkylaminosulfonylmethyl,mono-lower alkylaminosulfonylmethyl;hydroxy;mercapto;nitro;halogen;cyano;carboxamido or carboxhydrazido;N-mono- or N,N-disubstituted carboxamido;unsubstituted or substituted alkoxycarbonyl;unsubstituted or substituted alkoxy;formyl or other alkanoyl;unsubstituted or substituted alkenylor unsubstituted or substituted alkynyl;unsubstituted or substituted phenyl, preferably unsubstituted orsubstituted by one, two or three moieties independently selected fromthose mentioned above as substituents for substituted alkyl;or R₁ is a residue of a boronic acid or an ester thereof.

More preferred meanings of R1 include

unsubstituted or substituted heterocyclyl selected from the groupconsisting of unsubstituted or oxo- and/or lower alkyl-substitutedimidazolidinyl;

thienyl;

oxazolidonyl; such as imidazolidin-2,4-dionyl thienyl,5H-oxazol-2-on-4-yl, 2-methyl-4H-oxazolin-5-on-4-diyl;

pyrrolidinyl, such as pyrrolidin-1-yl, and triazolyl, such as1,2,4-triazol-1-yl; lower alkylsulfonyl;

sulfonyl-lower alkyl;

unsubstituted, N-mono- or N,N-di-lower alkyl substituted aminosulfonylalkyl;

hydroxy;

mercapto;

nitro;

halogen;

cyano;

carboxamido or carboxhydrazido;

N-mono- or N,N-disubstituted carboxamido, wherein the substitutents areindependently selected from lower alkyl and phenyl-lower alkyl;

unsubstituted or substituted alkoxycarbonyl where the substituents areindependently selected from lower alkyl and phenyl-lower alkyl;

unsubstituted or substituted alkoxy wherein the substitutents areindependently selected from lower alkyl or phenyl-lower alkyl;

formyl or other lower alkanoyl;

unsubstituted or lower-alkyl substituted lower alkenyl;

or unsubstituted or phenyl-lower alkoxy-substituted lower alkynyl;

or R₁ is a residue of a boronic acid or an ester thereof.

Of special technical importance are R₁ as halogen, cyano or nitro, e.g.chloro, bromo, iodo, cyano, nitro, especially standing in para-positionto the indole nitrogen. In the most preferred compounds, n is 1.

R3 and R4 usually are, independently of each other, unsubstituted orsubstituted alkyl, especially lower alkyl or phenyl lower alkyl, ortogether form an unsubstituted or substituted alkylene bridge,especially an unsubstituted or lower alkyl substituted lower alkylenebridge (thus forming a ring with the binding nitrogen).

Where R3 and R4 together form an un-substituted or substituted alkylenebridge (thus forming a ring with the binding nitrogen), the alkylenebridge preferably has 2 to 10, more preferably 3 to 6 carbon atoms, thusforming an 3 to 11 or, in the second case, 4 to 7-membered ring with thenitrogen to which they are bound, such as pyrrolidinyl; if substituentsare present, they are preferably selected from those mentioned aboveunder “substituted”, more preferably from lower alkyl, such as methyl,lower alkoxy, such as methoxy, or hydroxy. Where a phenyl orC₃-C₈-cycloalkyl ring is condensed to the alkylene bridge at two vicinalcarbon atoms, a bicyclic ring is formed bound via ring nitrogen.

R3 and R4 as an alkylene bridge, especially of 3 to 6 carbon atoms, maybe interrupted by oxygen or NH.

A preferred method for the synthesis of a compound of the formula I orpreferably II uses the above definitions of R1-R4 and n.

Especially preferred is the synthesis of a compound of the formula II,XII and/or XIV (see below), wherein n is 1 or 2, especially 1, R₁ isnitro or preferably halogen, especially chlorine, bromine or iodine, andR2, R3 and R4 are as defined above. Of special technical importance inthe synthesis of a substituted amide of the formula II (variant (b)) isa compound of formula II and a starting material wherein R1 is nitro,cyano, a residue of a boronic acid or ester thereof or halogen and n is1 or 2, where halogen is especially chloro, bromo or iodo; especiallypreferred is n=1 with R1 being in p-position to the oxindole nitrogen.

Where present in the novel compounds of the invention, R1 is oftenhalogen, a residue of a boronic acid or ester thereof, nitro or cyano,preferably cyano or halogen, more preferably wherein n is 1 and R₁ ishalogen, especially chloro, bromo or iodo; especially preferred is R₁ inp-position to the indole nitrogen.

These halogen-containing intermediates are readily available by thedescribed routes.

Novel compounds and/or intermediates of the above formulae I, II, III*,VII, VIII, IX, Xa, Xb, XI, and corresponding salts thereof, are anotherpreferred subject of the invention, e.g.

1) a compound of the formula I, or a salt thereof, wherein n is 1-4, and

each R₁ is unsubstituted or substituted alkyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heterocyclyl, sulfonylalkyl, N-mono- or N,N-disubstituted or unsubstituted aminosulfonylalkyl, hydroxy, mercapto, nitro, halogen, cyano, carboxamido, N-mono- orN,N-disubstituted carboxamido, carboxhydrazido, unsubstituted orsubstituted alkoxycarbonyl, unsubstituted or substituted alkoxy, formylor other alkanoyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,alkanoyloxy, N-mono- or N,N-disubstituted or unsubstituted amino,unsubstituted or substituted hydrazino, or is a residue of a boronicacid or an ester thereof;provided that when n is 1 and R₁ is lower alkyl, R₁ is located in theposition para to the isatine nitrogen (5-position),e.g. a compound as above with the exception of a compound of the formulaI wherein n is one and R₁ is lower alkyl;and with the further exception of a compound of the formula I wherein R₁is 5- or 7-chloro or 5- or 7-hydroxy or alkoxy or alkanoyloxy, and withfurther exception of the compound3-hydroxy-3-butyloxycarbonylmethyl-7-ethyl-6-hydroxy-indolidin-2-one.

Preferred compounds of the formula I, or salts thereof, are thosewherein n is 1 or 2, and each R₁ independently is bromo or iodo or nitroor cyano or hydroxy or a residue of a boronic acid or an ester thereof.

2) A compound of the formula II as defined above, or a salt thereof,e.g. wherein each R₁ independently is halogen or cyano or hydroxy or aresidue of a boronic acid or an ester thereof, preferably wherein R1 ishalogen, more preferably wherein n is 1 and R1 is halogen, especiallychloro, bromo or iodo, especially in p-position to the indole nitrogen;3) a compound of the formula III* as mentioned above, wherein n, R1 andR2 have the meanings given for compounds of the formula I or IIinitially described, except for a compound of formula I wherein n iszero or 1 and R1 is lower alkyl;4) a compound of the formula Xa as defined above, preferably wherein R1is halogen, cyano, more preferably wherein n is 1 and R1 is halogen,especially chloro, bromo or iodo, especially in p-position to the indolenitrogen;5) a compound of the formula Xb as defined above, preferably wherein R1is nitro or cyano or a residue of a boronic acid or an ester thereof, orhalogen, such as bromo, chloro or iodo, more preferably wherein n is 1and R1 is in p-position to the indole nitrogen;6) a compound of the formula XI, wherein n, R1 and R2 are as initiallydefined above, and where preferably R1 is nitro or cyano or a residue ofa boronic acid or an ester thereof or halogen, especially chloro, bromoor iodo, more preferably wherein n is 1, especially wherein R1 is inp-position to the oxindole nitrogen.

Also preferred is a compound of the formula IX as defined above.

Especially preferred are compounds of the formula II, III*, VII, VIII,Xa, Xb, XI and corresponding salts thereof. Where present, R₁ is oftenhalogen, nitro or cyano, preferably halogen; preferably with n being 1,especially preferred is R₁ in p-position to the indole nitrogen. Ofspecial technical importance is R1 as halogen, especially chloro, bromoor iodo.

These compounds (most of which are novel) are suitable for furtherfunctionalization, e.g. Suzuki-coupling, Sonogashira coupling, Kumadacoupling, cyanation, Heck coupling or alkoxy-carbonylation. Most ofthese products again are novel compounds, which can be further convertedinto derivatives of I.

Thus, it has been found that some of the above compounds, especially ofthe formula II, may be further reacted as described below. These arecompounds wherein

n, R₂, R₃ and R₄ are as defined above and, where present in case that nis not zero,

each R₁ is, independently, unsubstituted or substituted alkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheterocyclyl, alkylsulfonyl, sulfonyl alkyl, N-mono- orN,N-disubstituted or unsubstituted aminosulfonyl alkyl, hydroxy,mercapto, nitro, halogen, cyano, carboxamido, N-mono- orN,N-disubstituted carboxamido, unsubstituted or substitutedalkoxycarbonyl, unsubstituted or substituted alkoxy, formyl or otheralkanoyl, unsubstituted or substituted alkenyl, unsubstituted orsubstituted alkynyl, unsubstituted or substituted cycloalkyl,alkanoyloxy, N-mono- or N,N-disubstituted or unsubstituted amino, or isa residue of a boronic acid or an ester thereof (educt compounds, e.g.of the formula I or especially II).

In the below compounds XII to XX⁷, each R₁ preferably is, independentlyof any other substituent R₁ if present,

lower alkyl;

lower alkyl substituted by up to three moieties selected fromN,N-di-lower alkylamino, N-phenyl-lower alkylamino, N,N-bis(phenyl-loweralkyl)-amino, N,N-di-lower acylamino, N-lower acylamino;

halo-lower alkyl (e.g. trifluoromethyl);

C₃-C₁₀-cycloalkyl;

lower alkoxy, for example methoxy;

aryl-lower alkoxy, e.g. phenyl-lower alkoxy;

lower alkanoyloxy;

N,N-di-lower alkylamino;

N-phenyl-lower alkylamino, N,N-bis(phenyl-lower alkyl)-amino, each ofwhich contains phenyl unsubstituted or substituted, preferablyunsubstituted;

unsubstituted or substituted aryl;

unsubstituted or substituted heterocyclyl; unsubstituted or lower alkylsubstituted and/or mono- or di-oxosubstituted heterocyclenyl orheterocyclyl, e.g. imidazolidin-2,4-dionenyl or imidazolidin-2,4-dionylor thienyl;

alkylsulfonyl;

sulfonyl alkyl such as lower alkylsulfonylmethyl;

unsubstituted, N-mono- or N,N-disubstituted aminosulfonyl alkyl such aspyrrolidin-1-yl-sulfonylmethyl, di-lower alkylaminosulfonylmethyl,mono-lower alkylaminosulfonylmethyl;

hydroxy;

mercapto;

nitro;

halogen;

cyano;

carboxamido;

N-mono- or N,N-disubstituted carboxamido;

unsubstituted or substituted alkoxycarbonyl;

unsubstituted or substituted alkoxy;

formyl or other alkanoyl;

unsubstituted or substituted alkenyl

or unsubstituted or substituted alkynyl;

unsubstituted or substituted phenyl, preferably unsubstituted orsubstituted by one, two or three moieties independently selected fromthose mentioned above as substituents for substituted alkyl;

or R₁ is a residue of a boronic acid or an ester thereof.

More preferred meanings of R1 in these compounds include

unsubstituted or substituted heterocyclyl selected from the groupconsisting of unsubstituted or oxo- and/or lower alkyl-substitutedimidazolidinyl;

thienyl;

oxazolidonyl; such as imidazolidin-2,4-dionyl thienyl,5H-oxazol-2-on-4-yl, 2-methyl-4H-oxazolin-5-on-4-diyl;

pyrrolidinyl, such as pyrrolidin-1-yl, and triazolyl, such as1,2,4-triazol-1-yl;

lower alkylsulfonyl;

sulfonyl-lower alkyl;

unsubstituted, N-mono- or N,N-di-lower alkyl substituted aminosulfonylalkyl;

hydroxy;

mercapto;

nitro;

halogen;

cyano;

carboxamido;

N-mono- or N,N-disubstituted carboxamido, wherein the substitutents areindependently selected from lower alkyl and phenyl-lower alkyl;

unsubstituted or substituted alkoxycarbonyl where the substituents areindependently selected from lower alkyl and phenyl-lower alkyl;

unsubstituted or substituted alkoxy wherein the substitutents areindependently selected from lower alkyl or phenyl-lower alkyl;

formyl or other lower alkanoyl;

unsubstituted or lower-alkyl substituted lower alkenyl;

or unsubstituted or phenyl-lower alkoxy-substituted lower alkynyl;

or R₁ is a residue of a boronic acid or an ester thereof.

Especially preferred is the synthesis of a compound of the formula XIIand/or XIV (see below), wherein n is 1 or 2, especially 1, R₁ is nitroor preferably halogen, especially chlorine, bromine or iodine, and R2,R3 and R4 are as defined above. Of special technical importance in thesynthesis of a substituted amide of the formula II (variant (b)) is acompound of formula II as a starting material wherein R1 is nitro,cyano, a residue of a boronic acid or ester thereof or halogen and n is1 or 2, where halogen is especially chloro, bromo or iodo; especiallypreferred is n=1 with R1 being in p-position to the oxindole nitrogen.

Thus, in another embodiment of the invention, a compound of the formulaII wherein n, R₁ and R2 are as defined for educts as above; and R3 andR4 are, independently of each other, as defined under formula II,preferably are unsubstituted or substituted alkyl or together form anunsubstituted or substituted alkylene bridge (thus forming a ring withthe binding nitrogen), is reduced to a corresponding indole derivativein the presence of complex hydrides, preferably borane or boranederivatives,

In one preferred variant of this process, an educt compound of theformula II as just defined is reduced in the presence of a boranedi-lower alkyl sulfide (especially borane dimethyl sulfide) to give thecorresponding compound of the formula XII:

Surprisingly, here it is possible to retain the “dangling” amidefunctionality.

In an alternative variant, reaction of an educt compound of the formulaII as just defined in the presence of an alkali metal borohydride in thepresence of an boron trifluoride etherate yields a mixture of at leastthe following three compounds of the formulae XIIIa, XIIIb and XIIIc,

wherein n, R₁, R₂, R₃ and R₄ are as just defined for the startingcompounds of the formula II. Surprisingly, it is possible to convertthis mixture into a pure compound of the formula XIV

wherein n, R₁, R2, R3 and R4 are as defined under formula XIIIa, XIIIband XIIIc, which forms a further embodiment of the invention.

This can be accomplished by the reaction of a mixture of (XIIIa),XIIIb), and (XIIIc) with diazabicyclo[2.2.2]octane (DABCO) andsubsequent dehydrogenation or oxidation with an oxidant. The reactionsequence from the starting material of the formula II to the product ofthe formula XIV can take place without the need to isolate any of theintermediates, e.g. in one reaction vessel

In addition, for the intermediate compounds of the formulae I, II, VI,VII to XIV, conversion of functional groups may be made. These also formembodiments of the invention.

For example, in a compound of the formula XIV or XII, where R2 ishydrogen and the other moieties are as defined under these formulae, amoiety R2 other than hydrogen, that is unsubstituted or substitutedalkyl, unsubstituted or substituted alkoxycarbonyl, unsubstituted orsubstituted arylsulfonyl, unsubstituted or substituted alkylsulfonyl,unsubstituted or substituted aryl, carbamoyl, N-mono- orN,N-disubstituted carbamoyl, silyl substituted by three moietiesindependently selected from unsubstituted or substituted alkyl andsubstituted or unsubstituted aryl, or acyl may be introduced by standardreactions. Especially, unsubstituted or substituted alkyl is introducedby reaction with a strong base, e.g. NaH, with a correspondingunsubstituted or substituted alkyl derivative of the formula XV,Alk-L  (XV)wherein Alk is unsubstituted or substituted alkyl, for example benzyl,or unsubstituted or substituted alkoxycarbonyl, unsubstituted orsubstituted aryl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, andL is a leaving group, especially halogen, to give the correspondingcompound of the formula XII or XIV wherein R2 is unsubstituted orsubstituted alkyl, while acyl is introduced by reaction with thecorresponding acylhalogenides or mixed or symmetric acid anhydrides withone or two of the corresponding acyl moieties, while the silylderivatives are introduced using the corresponding silylhalogenides,e.g. silylchlorides, under standard reaction conditions, respectively.

In a compound of the formula II where n is zero and the othersubstituents are as defined above, halogen R₁ can be introducedresulting from substitution reaction with an electrophile, especiallyhalogen R₁ by reaction with halo-succinimides, or nitro by reaction withnitric acid, optionally in the presence of a strong dehydrating acid,e.g. sulfuric acid, leading to a compound of the formula XVI,

wherein Hal is a moiety resulting from electrophilic substitution,especially nitro or halogen, and R2, R3 and R4 have the meanings givenfor a compound of the formula II.

Thus, for example, halogenated compounds of this type (R1=halogen) withthe formulae II, XII or XIV can be converted into the correspondingcompounds wherein R1 is unsubstituted or substituted aryl by reactionwith a compound of the formula (A),Ar—BY₂  (A)wherein Ar is unsubstituted or substituted aryl and Y is OH, into thecorresponding compounds of the formulae II¹, XII¹ or XIV¹, respectively,

wherein n is 1 or 2, preferably 1, R₁ is unsubstituted or substitutedaryl and R2, R3 and R4 have the meanings given under formula (II) byreaction under the conditions of the Suzuki coupling or analogousconditions, i.e. by reaction in the presence of a base (especially analkalimetal carbonate, such as sodium or caesium carbonate, analkalimetal alcoholate, such as sodium ethanolate, an alkalimetalhydroxide, such as sodium hydroxide, a tertiary nitrogen base, such as atri-(lower alkyl)amine, e.g. triethylamine, or an alkali metalphosphate, such as sodium or potassium phosphate) and in the presence ofan appropriate palladium catalyst, especially allyltri-isopropyl-phosphino palladium bromide or Palladium acetate in thepresence of tri(ortho-tolylphosphine),bis-diphenylphosphino-ferrocenyl-palladium dichloride- or the like, inan appropriate solvent, e.g. in an ether, such as di-loweralkoxy-C₂-C₇-alkane, e.g. dimethoxyethane, preferably under an inertgas, e.g. argon, and preferably at elevated temperatures, e.g. between40° C. and reflux temperature, e.g. under reflux.

Thus, the invention provides a process for the manufacture of a compoundof the formula II¹, XII¹ or XIV¹, respectively,

wherein n is 1 or 2, R₁ is unsubstituted or substituted aryl orunsubstituted or substituted heterocyclyl, especially unsaturatedheterocyclyl (=heteroaryl) and R2, R3 and R4 have the meanings givenunder formula II, comprising reacting a compound of the formula II (forthe synthesis of compound II¹), XII (for the synthesis of compound XII¹)or XIV (for the synthesis of compound XIV¹) wherein in each case n is 1or 2, preferably one with the result that then also in the resultingcompound n is 1) and R1 is halogen, preferably chloro, bromo or iodo,preferably in para-position to the indole nitrogen, under the conditionsof the Suzuki coupling or analogous conditions with a compound of theformula (A),Ar—BY₂  (A)wherein Ar is unsubstituted or substituted aryl or heterocyclyl and Y isOH, into the corresponding compounds of the formulae II¹, XII¹ or XIV¹,respectively.

Alternatively, halogenated compounds of this type with the formulae II,XII or XIV (wherein R₁ is halogen) can be converted into thecorresponding compounds wherein R1 is unsubstituted or substitutedalkyn-2-yl by reaction with a compound of the formula (B),

wherein Z is unsubstituted or substituted (especially lower) alkyl,preferably aryl-lower alkoxymethyl, preferably benzyloxymethyl, to yieldthe corresponding compounds of the formulae II², XII² or XIV²,respectively,

wherein Z is as just defined and R2, R3 and R4 are as defined underformula (II), respectively. The reaction (a Sonogashira coupling)preferably takes place in the presence of CuI, a palladium catalyst,especially Pd(PhCN)₂Cl₂, a nitrogen base, e.g. piperidine, and atertiary phosphine, especially a tri-(lower alkyl) phosphine, such astri-(tert-butyl)phosphine, and in the presence of optional furthersolvents, such as lower alkanes, e.g. hexanes. The reaction preferablytakes place at elevated temperatures, e.g. between 30° C. and refluxtemperature, for example at 40 to 60° C.

As a third alternative, halogenated compounds of this type with theformulae II, XII or XIV can be converted into the correspondingcompounds wherein R1 is unsubstituted or substituted alken-2-yl byreaction with a compound of the formula (C),

wherein Z* is unsubstituted or substituted (especially lower) alkyl,unsubstituted or substituted aryl, unsubstituted or substitutedarylsulfonyl, unsubstituted or substituted alkylsulfonyl, (Y)₂N-sulfonylwherein each Y, independently of the other, is hydrogen or unsubstitutedor substituted alkyl, especially lower alkyl or preferably hydrogen,cyano, alkoxycarbonyl, preferably lower alkoxycarbonyl, e.g.methoxycarbonyl or ethoxycarbonyl, or unsubstituted or substitutedheterocyclyl (especially heteroaryl, that is, unsaturated heterocyclyl)under conditions of the Heck reaction, that is in the presence of apalladium catalyst, such as Pd (OAc)₂, PdCl₂, Pd(PPh₃)₄, Pd₂(dba)₃ orthe like and in the presence of a base, e.g. a tertiary nitrogen base,such as a tri-(lower alkyl)amine, e.g. triethylamine, an alkalimetalcarbonate, such as potassium carbonate, or an alkalimetal alcoholate,e.g. sodium ethanolate, to yield the corresponding compounds of theformulae II³, XVII³ or XIV³, respectively,

wherein Z* is as just defined and R2, R3 and R4 are as defined forcompounds of the formula II.

In a fourth alternative, halogenated compounds of this type of theformulae II, XII and XIV can be converted into the correspondingcompounds of the formulae II⁴, XII⁴ or XIV⁴,

wherein R2, R3 and R4 are as defined above for a compound of the formulaII, by reaction with a cyanide salt, especially a zinc cyanide, in thepresence of a palladium catalyst, e.g. Pd₂(dba)₃.CHCl₃.

In a fifth alternative, halogenated compounds of this type with theformulae II, XII and XIV can be converted into the correspondingcompounds of the formulae II⁵, XII⁵ or XIV⁵,

wherein R₅ is unsubstituted or substituted alkyl, especially loweralkyl, or unsubstituted or substituted aryl, especially phenyl, and R2,R3 and R4 are as defined above for a compound of the formula II, byreaction with CO in the presence of the corresponding alcohol R₅—OHwherein R₅ is as described above; the reaction preferably takes place inthe presence of a Palladium catalyst, especially Pd(dppp)Cl₂ and atertiary nitrogen base, e.g. a tri-lower alkylamine, such astriethylamine, preferably in a polar solvent, e.g. an alcohol, such asethanol, and in the presence of carbon monoxide at elevated pressure,e.g. between 10 and 50 bar, preferably at elevated temperatures, e.g.from 40 to 150° C., for example between 100 and 130° C., and preferablyin a pressure vessel.

In a sixth alternative, halogenated compounds of this type with theformulae XIV where R1 is halogen can be converted into the correspondingcompound of the formulae XX⁶,

wherein R2, R3 and R4 are as defined above for a compound of the formulaII, by reaction with first a lithium alkyl compound to form the lithiumderivative and then with DMF or triethyl formate, to obtain (XX⁶) afterhydrolysis. This intermediate offers further possibilities for thesynthesis of further tryptamine derivatives, for example as describedfor compounds of the formula, e.g. by Grignard reactions or otherreactions with the aldehyde function.

In these reactions, halogenated compounds of formulae II, XII or XIV areto be understood as those wherein R₁ is halogen such as Cl, Br, I,especially standing in para position to the indole nitrogen.

For example, the compound of the formula XX⁶ is converted into thecorresponding compound of the formula XXI,

wherein R2, R3 and R4 have the meanings indicated for compounds of theformula XX⁶, by reaction with a Wittig or Wittig Horner reagent, forexample alkyl triaryl phosphonium bromide, e.g. alkyl (e.g. methyl-)triphenyl phosphonium bromide, in the presence of a suitable base,preferably a strong base.

Alternatively, a compound of the formula XX⁶ is converted into thecorresponding hydroxymethyl compound of the formula XXI**,

wherein R2, R3 and R4 have the meanings indicated for compounds of theformula XX⁶, by reduction, for example with a reducing agent such assodium boro hydride in an alcohol or, lithium aluminium hydride in anether solvent or especially hydrogenation, in the presence of aselective transition metal catalyst, e.g. a Rhodium complex, such asRh[DIPFc(COD)]BF₄, (see J. Org. Chem. 2000, 65, 8933) or a Rutheniumcatalyst of the type (cis (PP) Ru trans (dichloro) cis(diamine), seeAngew. Chem. Int. Ed. 1998, 37, 1703) at elevated pressure, e.g. between2 and 300 bar, in a polar solvent, e.g. an alcohol, for example methanolor ethanol, at temperatures e.g. from 0 to 60° C., for example at roomtemperature.

In a seventh alternative, halogenated compounds of this type of theformulae XIV where R1 is halogen, can be converted into thecorresponding compound of the formula (XX⁷),

wherein R2, R3 and R4 are as defined above for a compound of the formulaII, by reaction with first a lithium alkyl compound to form the lithioderivative and then with an ester of boric acid B, to obtain (XX⁷),where R5 and R6 are a radical of an alcohol, e.g. lower alkoxy, ortogether are C₂-C₅alkylene-dioxy; preferred R5 independently are aresidue of a sterically hindered alcohol such as isopropoxy orpinakolyl, and R6 is isopropoxy Depending on the conditions at thework-up, also the boronic acid (R5=OH) may be obtained.

Novel compounds and/or intermediates of the above formulae XII, XIIIa,XIV, XVI, II¹, XII¹, XIV¹, II², XII², XIV², II³, XII³, XIV³, II⁴, XII⁴,XIV⁴, II⁵, XII⁵, XIV⁵, XX⁶, XXI* and XXI** and corresponding saltsthereof are another preferred subject of the invention, e.g.

7) a compound of the formula XII

wherein n, R₁, R₂, R₃ and R₄ are as defined for the educt compound offormula II, provided that R₁ is not 5-methoxy (i.e. methoxy in positionpara to the indole nitrogen) if n is 1; examples are compounds of theabove formula XII wherein R₁ is not methoxy if n is 1. Preferredcompounds of the formula XII are those wherein R₁ is nitro or cyano or aresidue of a boronic acid or an ester thereof, or is halogen, especiallychloro, bromo or iodo, more preferably wherein n is 1, especially inpara-position to the indole nitrogen;8) a compound of the formula XIIIa as defined above, preferably whereinR1 is nitro or cyano or a residue of a boronic acid or ester thereof oris halogen, especially iodo in para-position to the indole nitrogen andn is 1;9) a compound of the formula XIV

wherein n, R2, R3 and R4 are as defined above and R₁ is a residue of aboronic acid or ester thereof, lower alkyl, lower alkyl substituted byup to three moieties selected from N,N-di-lower acylamino and N-loweracylamino, C₃-C₁₀-cycloalkyl, C₂-C₄alkoxy, nitro, halogen, loweralkanoyloxy such as C₁-C₄alkanoyloxy, unsubstituted or substituted aryl(e.g. phenyl), unsubstituted or lower alkyl substituted and/or mono- ordi-oxosubstituted nitrogen-heterocyclenyl or nitrogen-heterocyclyl suchas imidazolidin-2,4-dionenyl or imidazolidin-2,4-dionyl, sulfonyl alkylsuch as lower alkylsulfonylmethyl, mercapto, C₂-C₈alkanoyl,unsubstituted or substituted alkenyl, or unsubstituted or substitutedalkynyl, or a salt thereof; preferably wherein R1 is a residue of aboronic acid or ester thereof, C₃-C₁₀-cycloalkyl, unsubstituted orsubstituted phenyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl. Of special technical interest is a compound ofthe formula XIV wherein R₁ is nitro or halogen, more preferably whereinn is 1 and R1 is nitro or iodo, especially in p-position to the indolenitrogen, or a salt thereof;10) a compound of the formula II¹, XII¹ or XIV¹ as defined above, or asalt thereof;11) a compound of the formula II², XII² or XIV², as defined above, or asalt thereof,12) a compound of the formula II³, XII³ or XIV³ as defined above, or asalt thereof,13) a compound of the formula II⁴ or XII⁴ as defined above, or a saltthereof,14) a compound of the formula II⁵ or XII⁵, as defined above, or a saltthereof,15) a compound of the formula XIV⁵,

wherein R2, R3, R4 and R₅ are as defined above, provided that one of R3or R4 is not methyl and R3 and R4 together are not phthalyl, or a saltthereof. In a preferred compound of the formula XIV⁵, R3 and R4 are,independently of each other, C₂-C₄alkyl or phenylmethyl orphenyl-C₂-C₄alkyl, whose phenyl rings may be substituted orunsubstituted, or together form an unsubstituted or substituted alkylenebridge of 3 to 6 carbon atoms which may be interrupted by oxygen or NH;if substituents are present, they are preferably selected from thosementioned below under “substituted”, more preferably from lower alkyl,such as methyl, lower alkoxy, such as methoxy, or hydroxy.16) A compound of the formula XX⁶

wherein R2, R3, R4 and R₅ are as defined above, provided that one of R3or R4 is not methyl and R3 and R4 together are not phthalyl, or a saltthereof. In a preferred compound of the formula XIV⁵, R3 and R4 are,independently of each other, C₂-C₄alkyl or phenylmethyl orphenyl-C₂-C₄alkyl, whose phenyl rings may be substituted orunsubstituted, or together form an unsubstituted or substituted alkylenebridge of 3 to 6 carbon atoms which may be interrupted by oxygen or NH;if substituents are present, they are preferably selected from thosementioned below under “substituted”, more preferably from lower alkyl,such as methyl, lower alkoxy, such as methoxy, or hydroxy.17) A compound of the formula XX⁷ as defined above, or a salt thereof,18) a compound of the formula XXI* as defined above, or a salt thereof,19) a compound of the formula XXI** as defined above, or a salt thereof.

Especially preferred are compounds of the formula XII, XIIIa, XVI, II¹,XII¹, XIV¹, II², XII², XIV², II³, XII³, II⁴, XII⁴, II⁵, XII⁵, XIV⁵, XX⁷,XXI* and XXI** and corresponding salts thereof. Where present, R1 isoften halogen, nitro or cyano or a residue of a boronic acid or an esterthereof, preferably halogen; preferably with n being 1, especiallypreferred is R₁ in p-position to the indole nitrogen. Of specialtechnical importance is R1 as halogen, especially chloro, bromo or iodo.

Unless otherwise indicated, the general terms and names used in thedescription of the present invention preferably have the followingmeanings (where more specific definitions, in each case separately, orin combination, may be used to replace more general terms in order todefine more preferred embodiments of the invention):

Where compounds are mentioned, this means these compounds or saltsthereof, e.g., where in the compounds acidic groups are present, saltswith bases, such as alkali metal salts or ammonium salts, where basicgroups are present, acid addition salts, e.g. with inorganic acids, suchchlorides or sulfates, or with organic acids, e.g. sulfonic or carbonicacids, such as methane sulfonates or acetates, where appropriate andexpedient. Where both acidic and basic groups are present, also internalsalts may be formed.

Preferred salts of the compounds of the invention are acid additionsalts such as hydrohalogenides (hydrochlorides), hydrocarbonates, oracylic acid salts like oxalates, fumarates, acetates, citrates and thelike.

The term “lower” defines a moiety with up to and including maximally 7,especially up to and including maximally 4, carbon atoms, said moietybeing branched or straight-chained. Lower alkyl, for example, is methyl,ethyl, n-propyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, n-hexyl or n-heptyl.

Halogen or halo is preferably fluoro, chloro, bromo or iodo, mostpreferably chloro; bromo or iodo (if not stated otherwise).

In “un-substituted or substituted”, “substituted”, wherever used for amoiety, means that one or more hydrogen atoms in the respectivemolecule, especially up to 5, more especially up to three, of thehydrogen atoms are replaced by the corresponding number of substituentswhich preferably are independently selected from the group consisting ofalkyl, especially lower alkyl, for example methyl, ethyl or propyl,hydroxy, mercapto, nitro, cyano, halo, halo-lower alkyl, for exampletrifluoromethyl, C₆-C₁₆-aryl, especially phenyl or naphthyl (whereC₆-C₁₆-aryl, especially phenyl or napthyl, is unsubstituted orsubstituted by one or more, especially up to three moieties selectedfrom N,N-di-lower alkylamino, N-phenyl-lower alkyl-amino,N,N-bis(phenyl-lower alkyl)-amino, and halo-lower alkyl, e.g.trifluoromethyl), C₃-C₁₀-cycloalkyl, lower alkoxy, for example methoxy,aryl-lower alkoxy, e.g. phenyl-lower alkoxy, lower alkanoyloxy,N,N-di-lower alkylamino, N-phenyl-lower alkylamino, N,N-bis(phenyl-loweralkyl)-amino, di-lower alkylamino, unsubstituted or lower alkylsubstituted and/or mono- or di-oxosubstituted heterocyclylenyl orheterocyclyl, e.g. unsubstituted or lower alkylsubstituted-imidazolidin-2,4-dionenyl or imidazolidin-2,4-dionyl. Itgoes without saying that substitutents are only at positions where theyare chemically possible, the person skilled in the art being able todecide (either experimentally or theoretically) without inappropriateeffort which substitutions are possible and which are not.

In unsubstituted or substituted alkyl, alkyl preferably has up to 20,more preferably up to 12 carbon atoms and is linear or branched one ormore times; preferred is lower alkyl, especially C₁-C₄-alkyl.Substituted alkyl is especially lower alkanoyoxy-lower alkyl, such asacetoxymethyl, aryl-lower alkyl, especially benzyl, unsubstituted ormono- or di-oxo-substituted heterocyclylenyl-lower alkyl orheterocyclyl-lower alkyl, hydroxy-lower alkyl, e.g. hydroxy-methyl,mercapto-lower alkyl, e.g. mercaptomethyl, lower alkyl or lower alkyland oxo substituted heterocyclenyl-lower alkyl, e.g.lower-alkyl-substituted 4H-oxazol-5-on-enyl, or lower alkanoyloxy-loweralkyl, e.g. acetoxymethyl,

In unsubstituted or substituted cycloalkyl, cycloalkyl usually has 3 to12 carbon atoms; thus, cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, cyclododecyl. Substituents, where present, areas defined above for alkyl substituents.

In unsubstituted or substituted aryl, aryl (also in arylene) preferablyhas a ring system of not more than 24 carbon atoms, especially not morethan 16 carbon atoms, is preferably mono-, bi- or tric-cyclic, and isunsubstituted or substituted preferably as defined above under“Substituted”; for example, aryl is selected from phenyl, naphthyl,indenyl, azulenyl and anthryl, and is preferably in each caseunsubstituted or substituted phenyl. Aryl, preferably phenyl, isespecially preferred.

In unsubstituted or substituted heterocyclyl, heterocyclyl is preferablya heterocyclic radical that is unsaturated, saturated (then heterocyclylis heteroaryl, that is, if the maximum possible number of double bondsis present in the ring) or partially saturated in the bonding ring andis preferably a monocyclic or in a broader aspect of the inventionbicyclic or tricyclic ring; has 3 to 24, more preferably 4 to 16 ringatoms; wherein at least in the ring bonding to the radical of themolecule of formula I one or more, preferably one to four, especiallyone or two carbon ring atoms are replaced by a heteroatom selected fromthe group consisting of nitrogen, oxygen and sulfur, the bonding ringpreferably having 4 to 12, especially 5 to 7 ring atoms; heteroarylbeing unsubstituted or substituted by one or more, especially 1 to 3,substitutents independently selected from the group consisting of thesubstituents defined above under “Substituted” and/or by one or more oxogroups; especially being a heteroaryl radical selected from the groupconsisting of imidazolyl, thienyl, furyl, pyranyl, thiopyranyl,benzofuranyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, benzimidazolyl,pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, oxazolyl, pyridyl,pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl,morpholinyl, thiomorpholinyl, indolizinyl, isoindolyl, indolyl,benzimidazolyl, indazolyl, triazolyl, isoquinolyl, quinolyl,tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dibenzofuranyl,benzothiophenyl, dibenzothiophenyl, naphthyridinyl, quinoxalyl,quinazolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl andphenoxazinyl, each of these radicals being unsubstituted or substitutedby one to three radicals selected from the group consisting of loweralkyl, especially methyl or tert-butyl, and oxo. Especially preferredare unsubstituted or oxo- and/or lower alkyl-substituted imidazolidinyl,thienyl, oxazolidonyl, triazolyl or pyrrolidinyl such asimidazolidin-2,4-dionyl, thienyl, oxazol-on-yl,2-methyl-4H-oxazol-5-onyl, pyrrolidin-1-yl or 1,2,4-triazolyl.

In unsubstituted or lower alkyl substituted and/or mono- ordi-oxosubstituted heterocyclylenyl or heterocyclyl, heterocyclyl ispreferably as defined above. Heterocyclylenyl means a heterocyclylmoiety bound to the rest of the molecule by a double bond, whileheterocyclyl is bound via a single bond. Preferred are unsubstituted orlower alkyl substituted-4H-oxazol-5-on-enyl, or the moieties mentionedas preferred for unsubstituted or substituted heterocyclyl.

In Alkylsulfonyl, alkyl is preferably as defined above; preferred islower alkylsulfonyl, such as methanesulfonyl.

In Sulfonyl alkyl, alkyl is preferably as defined above; preferred issulfonyl-lower alkyl, such as sulfonylmethyl.

In unsubstituted or substituted arylsulfonyl, unsubstituted orsubstituted aryl is preferably as defined above, e.g. lower-alkylsubstituted phenyl; preferred is toluylsulfonyl.

In unsubstituted or substituted alkylsulfonyl, unsubstituted alkyl ispreferably as defined above, preferably lower alkyl; preferred is loweralkylsulfonyl, e.g. methanesulfonyl.

In N-mono- or N,N-disubstituted or unsubstituted aminosulfonyl alkyl,the substituents are preferably selected from those mentioned aboveunder “substituted”, especially aryl or heterocyclyl, such aspyrrolidinyl, while alkyl is preferably as defined above, especiallylower alkyl, such as methyl. Aminosulfonyl alkyl is preferablyaminosulfonyl lower alkyl, especially aminosulfonylmethyl.

In N-mono- or N,N-disubstituted carboxamido, the substituents if presentare preferably selected from unsubstituted or substituted alkyl,especially lower alkyl, such as lower alkyl or phenyl-lower alkyl, e.g.benzyl. For example, carboxamido may stand for a residue —CO—NR₂₃R₂₄,wherein R₂₃ and R₂₄ independently are H, lower alkyl, lower alkenyl,lower alkyl or alkenyl substituted by OH or oxo; or R₂₃ and R₂₄ togetherform a C₃-C₁₁ alkylene or alkenylene which is unsubstituted orsubstituted by OH or oxo, especially by 1 or 2 groups ═O. Consequently,carboxhydrazido embraces a residue —CO—NH—NR₂₃R₂₄, wherein R₂₃ and R₂₄independently are as defined above.

Hydrazino embraces a residue of the formula R₂₀R₂₁N—N(R₂₂)— wherein R₂₀is alkyl or acyl or substituted alkyl (e.g. benzyl) and R₂₁ is hydrogenor R₂₀ and R₂₂ is hydrogen or acyl.

In unsubstituted or substituted alkoxycarbonyl, the substituents ifpresent are preferably selected from unsubstituted or substituted alkyl,especially lower alkyl, such as lower alkyl or phenyl-lower alkyl, e.g.benzyl.

In unsubstituted or substituted alkoxy, the substituents are preferablyselected from alkyl, especially as defined above, preferably loweralkyl, or phenyl-lower alkyl, e.g. benzyl.

Acyl is preferably a linear, branched, cyclic, cyclic-linear, saturatedor partially or totally unsaturated organic carboxylic acid radical,especially unsubstituted or substituted alkoxycarbonyl, unsubstituted orsubstituted aryloxycarbonyl, unsubstituted or substituted aryl-loweralkoxycarbonyl, or preferably aryl-carbonyl, aryl-lower alkylcarbonyl or(unsubstituted or substituted alkyl)-carbonyl wherein aryl, alkyl andthe substituents if present are preferably as defined above. Preferredis lower alkanoyl, especially acetyl.

In formyl or other alkanoyl, alkanoyl is preferably lower alkanoyl, suchas acetyl,

In unsubstituted or substituted alkenyl, alkenyl is preferably a moietywith up to 20 carbon atoms, preferably lower alkenyl, wherein one ormore, especially one, double bonds are present. If substituents arepresent, they are mainly selected from those given above under“Substituted” where chemically possible, as can be deduced convenientlyby the person skilled in the art. In unsubstituted or substitutedalkynyl, alkynyl preferably has up to 20 carbon atoms; more preferred islower alkynyl. If substituents are present, they are mainly selectedfrom those given above under “Substituted” where chemically possible, ascan be deduced conveniently by the person skilled in the art. Especiallypreferred is aryl-lower alkoxy-lower alkynyl, such as3-benzyloxy-2-propynyl.

In unsubstituted or substituted alkoxycarbonyl, alkoxy is preferably asdefined above, especially lower alkoxy, such as methoxy, while thesubstitutents, if present, are preferably chosen from those mentionedabove, especially lower alkyl, or aryl-lower alkyl, such as benzyl.Preferred is tert-butoxycarbonyl or benzyloxycarbonyl.

In N-mono- or N,N-disubstituted carbamoyl, the substituents arepreferably selected from those mentioned above under “substituted”, morepreferably from lower alkyl, and aryl-lower alkyl, such as benzyl.

In silyl substituted by three moieties independently selected fromunsubstituted or substituted alkyl and substituted or unsubstitutedaryl, “unsubstituted or substituted”, “alkyl” and “aryl” preferably havethe meanings given above; preferred is tri-(lower alkyl)-silyl, such astrimethylsilyl or tert-butyl-dimethylsilyl.

A tertiary nitrogen base NB where the nitrogen is not part of a ring ispreferably a nitrogen substituted by three moieties selected from alkyl,such as lower alkyl, especially ethyl, C₃-C₇-cycloalkyl, such ascyclohexyl, or phenyl-lower alkyl, such as benzyl. Preferred as base NBare N,N-dicyclohexyl-N-lower alkylamines, such asdicyclohexyl-ethylamine, or especially tri-lower alkylamines, such astriethylamine.

An active carbonic ester of the formula IV, wherein X is halogen, isespecially the corresponding bromide or especially chloride.

Unsubstituted or substituted alkyl for R′ is preferably as defined abovein general, more preferably selected from lower alkyl or phenyl-loweralkyl, such as methyl, ethyl or benzyl.

An active amido carbonic acid derivative of the formula V, wherein X ishalogen, is preferably the chloride.

The reactions presented above and below in general terms are conductedunder standard conditions for the person skilled in the art forcorresponding known reactions. In detail, the following reactionconditions are preferred:

Reaction of a compound of the formula VI with malonic acid in thepresence of a pyridine, especially a picoline or most especiallypyridine, in an N,N-(di-lower alkyl)-lower alkanoylamide, preferablydimethylformamide (DMF) followed by conversion into the salt of the baseNB given in formula III, preferably takes place at temperatures between30° C. and reflux temperature, e.g. between 50 and 90° C., for examplebetween 60 and 80° C.

Preferably, the reaction of the compound of the formula VI with malonicacid in the presence of a pyridine, and the subsequent conversion intothe salt of the formula III with the base NB and reaction a) or b) abovetake place in the same reaction vessel (one pot synthesis), that is,without isolation of the intermediate product of the formula III.

For the conversion of a compound of the formula II into a compound ofthe formula VII, the reaction preferably takes place in acetic acid inthe presence of an acidic catalyst, preferably an inorganic acid,especially sulphuric acid, phosphoric acid, or hydrogen bromide,preferably at elevated temperatures, e.g. between 50 and 100° C., and inthe presence of a small amount of water.

For the transformation of a compound of the formula VII into thecorresponding free alcohol of the formula VIII, hydrolysis in thepresence of a base and water or trans-esterification in the presence ofan alcohol, e.g. a lower alkanol, such as methanol or ethanol, and abase, e.g. an alkali metal salt base, such as an alkali metal carbonate,e.g. sodium or potassium carbonate, or the alkali metal salt of anorganic acid, e.g. an alkali metal lower alkanoate, such as sodiumacetate, at elevated temperatures, e.g. between 60° C. and the refluxtemperature of the reaction mixture, for example between 80° C. andreflux temperature, is preferred. The reaction can also take placewithout isolation of the compound of the formula VII.

In the reaction of a compound of the formula II wherein R2 has one ofthe meanings given above with a dehydrating agent, preferably an acidanhydride (preferably an anhydride of a lower alkanoic acid, especiallyacetic anhydride) to give a compound of the formula Xa, the reactionpreferably takes place in this solvent, at elevated temperatures,especially under reflux.

If desired, reduction of the resulting compound of the formula Xa in thepresence of a reductant (especially hydrogen in the presence of acatalyst, such as a noble metal catalyst with or without a carrier, e.g.Pd or Pd on charcoal, or hydrogen in statu nascendi, which is generatedby a reactive (non-noble) metal, especially zinc) to a compound of theformula Xb then preferably takes place in the presence of an organicacid, especially acetic acid, at elevated temperatures, e.g. between 50°C. and the reflux temperature of the reaction mixture, for example underreflux.

For the alternative embodiment of the invention where a compound of theformula Xa is obtained by hydrogenation of a compound of the 3-hydroxygroup in a compound of the formula II, the hydrogenation preferablytakes place with hydrogen in the presence of a catalyst, especially anoble metal catalyst with or without carrier, such as Pd or Pd oncharcoal, under standard reaction conditions.

The conversion of a compound of the formula Xb to a spiro indole of theformula XI by reaction with formaldehyde preferably takes place in alower alcohol such as methanol or ethanol at elevated temperatures, e.g.between 50° C. and reflux temperature.

For the reaction where a compound of the formula II is reduced to acorresponding indole derivative in the presence of complex hydrides,e.g. lithium aluminium hydride (for reaction conditions see J. Org.Chem. 53, 2844 (1988) or J. Med. Chem. 31, 1244 (1988)) or preferablyborane or borane derivatives (see e.g. Tetrahedron: Asymmetry 7, 285,1996) are used, advantageously under borane generation in situ,especially takes place in an appropriate solvent, such as an ether, e.g.a di-lower alkoxy lower alkane, such as dimethoxy ethane,di-ethylenglycol-di-methyl ether or THF, in the case of use of aborohydride derivative, e.g. an alkali metal borohydride, such as sodiumborohydride, preferably in the presence of a boron trifluoride complex,e.g. BF₃ etherate (the complex with diethyl ether), preferably atelevated, ambient or slightly lowered temperatures, e.g. between −30 and+50° C., especially between −30 and 28° C.

In the variant with presence of a borane di-lower alkyl sulfide(especially borane dimethyl sulfide) to give the corresponding compoundof the formula XII, the reaction preferably takes place in anappropriate solvent, e.g. an ether, for example a di-lower alkoxy loweralkane, such as dimethoxy ethane, in the presence of a boron trifluoridecomplex, e.g. BF₃ etherate, especially at lowered, ambient and/orelevated temperature, preferably temperatures between −10° C. and 80° C.

In the embodiment of the invention where the reaction with an alkalimetal borohydride in the presence of an boron trifluoride etherateyields a mixture of three compounds of the formulae XIIIa, XIIIb andXIIIc, the reaction preferably takes place in an appropriate solvent,e.g. the presence of an ether, for example a di-lower alkoxy loweralkane, such as dimethoxy ethane, at preferred temperatures between −20and 50° C., e.g. between −15 to 30° C., and the subsequent reaction withDABCO (which can preferably follow without isolation of the mentionedproduct mixture, that is, as one pot reaction, after addition of a metalsalt base, e.g. an alkali metal hydroxide in water, such as sodium orpotassium hydroxide) at elevated temperatures, e.g. between 50° C. andreflux temperature, for example at about 80° C. After partial isolationfrom the inorganic phase, preferably with some additional extractionsteps, the products are dissolved in an appropriate solvent, e.g. anether, such as a di-lower alkyl ether, e.g. tert-butyl-methyl-ether, andoxidized with an appropriate oxidant, e.g. as mentioned above,especially manganese dioxide, at preferred temperatures between 10° C.and the reflux temperature, e.g. between 20 and 50° C.

The conversion in a compound of the formula XIV or XII, where R2 ishydrogen and the other moieties are as defined under these formulae, tointroduce a moiety R2 other than hydrogen, in the presence of sodiumhydride with a corresponding unsubstituted or substituted alkylderivative of the formula XXI preferably takes place in an appropriatesolvent, such as an N,N-di-(lower alkyl)-lower alkanoylamide, e.g.N,N-dimethylformamide, at appropriate temperatures, e.g. between −10 and40° C., preferably under an inert gas, such as nitrogen.

The reaction for the introduction of a moiety resulting fromelectrophilic substitution, especially nitro or halogen, especiallychloro R₁ into a compound of the formula II, takes place under standardconditions for the introduction of such groups, for example by reactionwith halo-succinimides, especially N-chloro succinimide leading to thecorresponding halogenated compound of the formula XVI, preferably takesplace in an appropriate solvent or solvent mixture, e.g. a loweralkanoic acid, e.g. acetic acid, dichloroethane, and/or an aromaticsolvent, e.g. chlorobenzene, at customary temperatures, e.g. attemperatures between 20 and 30° C., for the introduction of nitro byreaction with HNO₃, optionally in the presence of sulfuric acid oracetic acid.

The reaction of a compound of the formula XX⁶ into the correspondingcompound of the formula XXI preferably takes place in an appropriatesolvent, e.g. an ether, such as tetrahydrofurane, preferably under inertgas, e.g. argon or nitrogen, at preferred temperatures from −10° C. tothe reflux temperature of the mixture, e.g. from 15 to 40° C., e.g. atroom temperature. As strong base, preferably an alkoholate salt is used,e.g. an alkali metal lower alkoxide, such as sodium or potassiumtert-butoxide. The invention also relates to the single reaction stepsof the reactions mentioned above, as well as combinations of two or morethereof as far as they are consecutive steps in a reaction sequence, aswell as novel intermediates.

The formation of compounds of the formula XX⁷ preferably takes place atlower temperatures, e.g. in the range of about −170° C. to about roomtemperature, especially between about −100 and 0° C. It is preferablycarried out under exclusion of moisture and oxygen, e.g. under inertatmosphere, and in an appropriate solvent such as ether (e.g. diethylether). Lithium alkyls usable are those commonly known in the art, e.g.butyllithium. Preferred boron compounds are as initially described.Workup with hydrolysis may be carried out under conditions as commonlyknown, e.g. ambient conditions.

Where necessary and appropriate, in any of the reactions shown aboveprotecting groups may be introduced and removed at appropriate reactionstages which allow to protect functional groups that are intended not toparticipate in the respective reaction reversibly. Examples ofprotection groups, their introduction and their removal are presented inT. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, 3^(rd) edition, John Wiley & Sons, Inc., New York/Weinheim1999, which is herewith incorporated by reference in respect to theprotection groups, their removal and their introduction, respectively.

Starting materials for which the synthesis is not mentioned in thepresent disclosure are either commercially available, prepared accordingto standard methods or known in the art.

Preferred Embodiments of the Invention

The invention relates to the single reaction steps as given above, aswell as any combination of two or more reaction sequence steps that arein succession, that is, where the product of one reaction is theprecursor of the next reaction that is part of such combination.

Preferred embodiments of the invention can be found in the claims, whichare incorporated here by reference, the dependent claims representingpreferred embodiments of the invention. In the claims, more generaldefinitions can be replaced with the more specific definitions givenabove, independently or together with some or all other generalexpression, thus leading to further preferred embodiments of theinvention.

Highly preferred embodiments of the invention are those where in theprocesses mentioned above the formulae represented above are replacedwith the corresponding specific compounds mentioned in the examples.

Very preferred process steps, combinations of process steps, novelstarting materials and intermediates (compounds) that are part of thepresent invention are described in the subsequent examples, thus formingvery preferred embodiments of the invention.

EXAMPLES

The following examples serve to illustrate the invention withoutlimiting the scope thereof. Wherever ambient temperature or roomtemperature is mentioned, this denotes a temperature in the range 20-25°C. unless stated otherwise.

Example 1 Preparation of2-(5-Bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

A 2 L flask fitted with an inner thermometer, mechanical stirrer, andreflux condenser is charged with 5-bromo-isatin (100 g, 0,442 mol),malonic acid (55.2 g, 053 mol), pyridine (100.6 g, 1.274 mol), dimethylformamide (80 g), and ethyl acetate (100 g). When the temperature of themixture reaches 60° C., the bromo isatin starts to dissolve, and a deepred mixture forms, Carbon dioxide starts to evolve, and after about 45minutes the precipitation of the intermediate pyridinium(5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-acetate starts. Thereaction mixture is kept at 80° C. for another 3 hours. Then triethylamine (49.2 g, 0.486 mol) is added, and the pyridinium salt dissolves togive a deep brown solution. This solution is allowed to cool to 50° C.,and then a solution of dimethyl carbamoyl chloride (48 g, 0.442 mol,CAUTION: carcinogen) in 40 g of ethyl acetate is added dropwise during30 minutes. Carbon dioxide evolves, and the temperature rises to 60° C.After about 45 minutes, the product starts to precipitate from thereaction mixture. The mixture is kept at 60° C. for another hour, andthen water (500 mL) and 36% HCl (250 mL, 4 mol) are added in that orderduring 10 minutes. The product is filtered off, and reslurried in anmixture of acetone/water (500 mL, 1:1, v:v). The slurry is filteredagain, and the product is finally dried to give the title compound as agray powder which is of suitable purity for direct use in the furthersteps. Yield: 75.2 g (54.2%). An analytically pure sample is obtained byrecrystallization from methanol, mp=245-246° C., dec. ¹H-NMR (DMSO-D6,300 MHz): δ 2.64 (s, 3, CH₃), 2.93 (s, 3, CH₃), 2.93, 3.27 (AB, 2,²J=16.5 Hz, CH₂), 6.01 (br s, 1, OH), 6.73 (d, 1, J=8.2 Hz, H-7), 7.30(dd, 1, ³J=2.0 Hz, H-6), 7.42 (d, 1, H-4), 10.18 (br s, 1, NH). ¹³C-NMR(DMSO-D6, 75 MHz) δ 35.04, 37.45 (N(CH₃)₂), 40.78 (CH₂), 73.90 (C-3),111.85 (C-7), 113.29 (C-5), 127.03 (C-4), 131.83 (C-6), 135.78 (C-9),143.18 (C-8), 168.93 (CONMe₂), 178.68 (C-2).

Example 2 Preparation of2-(5-Bromo-1H-indol-3-yl)-N,N-dimethyl-acetamide

A 1 L flask fitted with an inner thermometer, mechanical stirrer anddropping funnel is charged with 34.8 g of2-(5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1.H.-indol-3-yl)-.N,N.-dimethyl-acetamide(0.111 mol) and 250 mL of dimethoxy ethane (DME). The obtainedsuspension is cooled with an ice bath, and then BF₃-etherate (28.3 g,0.2 mol) is added while the inner temperature is maintained at 20° C.This leads to the formation of a solution after a few minutes. Thetemperature is kept at 20° C., and 12.0 g of 95% borane dimethylsulfidecomplex (0.15 mol) is added dropwise during 10 minutes. The cooling bathis then removed, and the temperature of the mixture rises slowly, whilea gas is formed. When the temperature reaches 48° C., the product startsto precipitate whilst the temperature continues to rise until it reaches58° C. After about 10 minutes the temperature starts to fall to ambienttemperature. After 75 minutes, the reaction mixture is quenched with 100mL of 4 N NaOH (no exothermic reaction), and then the obtained olivegreen suspension is heated under reflux for 30 minutes. After cooling toambient temperature, the mixture is filtered, and most of the DME isremoved from the filtrate by rotary evaporation (rotavapor). To theresidue, acetone (about 100 mL) is added, and the product is allowed tocrystallize at 4° C. for 30 minutes. The crude product is filtered offand washed with little acetone and pentane to give 22.2 g of beigecrystals. These are purified by crystallization from methanol/Norite(activated charcoal) (385 mL, 2.2 g) to give 16.2 g of colorlesscrystals. The residue obtained after removal of the solvent isrecrystallized from methanol/Norite (75 mL/1.2 g) to give a second cropof 3.0 g. Combined yield of the title compound (19.2 g, 61.4%),mp=201-202° C. ¹H-NMR (DMSO-D6, 300 MHz) δ 2.80, 3.00 (2 s, 3H eachN(CH₃)₂); 3.71 (s, 2H, CH₂); 7.15 (dd, 1H, 3J=8.5 Hz, 4J=2 Hz, H-6);7.25 (d, 1H, J=2.3 Hz, H-2); 7.30 (d, 1H, H-7); 7.73 (d, 1H, H-4); 11.09(br s, 1H, NH). ¹³C-NMR (DMSO-D6, 75 MHz): δ 31.12 (CH₂); 35.68, 37.91(CH₃); 108.88, 111.71, 113.99 (CH), 121.98 (CH), 124.09 (CH), 125.97(CH), 129.93, 135.54, 171.00 (CO).

Example 3 Preparation of[2-(5-Bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine

A 1 L flask is charged with2-(5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide(Example 1) (31.2 g, 0.1 mol), sodium borohydride (11.8 g 96%, 0.3 mol),and 250 mL of dimethoxyethanol (DME). The mixture is cooled to −15° C.,and to the stirred suspension, BF₃-etherate (56.6 g, 0.4 mol) is addeddropwise. The temperature is maintained between −15 and −10° C. duringthe exothermic addition. The mixture is then allowed to warm slowly toambient temperature (25-27° C.), and left stirring over night. Themixture is cooled with an ice bath and quenched by the addition of 4NNaOH (200 mL). The formed viscous emulsion is heated to 80° C. for 30minutes, then diazabicyclo[2.2.2]cyclooctane (DABCO) (12.7 g 97%, 0.11mol) is added, and then the mixture is heated for two additional hoursunder reflux. After cooling to ambient temperature, the aqueous layer isremoved and the organic layer is extracted twice with each 50 mL of a 4N NaOH.solution. After re-extraction of the combined inorganic layerswith toluene (150 mL), the aqueous phase is disposed off, and thetoluene layer is added back into the reaction vessel. To the vessel,additional toluene (150 mL) is added and the mixture is then extractedwith water (200 mL). The aqueous layer is separated, and extracted twicewith each 150 mL of toluene. After disposal of the inorganic thecombined toluene layers are extracted for three times with water (300mL, 2×150 mL), and the aqueous layer is again discarded. The toluenelayer is then extracted twice with 4N HCl (100 mL and 50 mL). During thecombined acidic extracts, the pH is then adjusted to 14 by the additionof 4 N NaOH. Then the aqueous layer is extracted twice with tert-butylmethyl ether TBME (150 mL and 50 mL), and the combined extracts arewashed with brine (50 mL) and then transferred into a 500 mL flask. Tothe stirred TBME solution, MnO₂ (34.8 g, 0.4 mol) is then added, andtemporarily the temperature rises to 40° C. After one hour the anilineby-product has been converted completely, and then the MnO₂ is filteredoff. Removal of the solvent from the filtrate gives the title product asa colourless viscous oil which crystallizes (23.85 g, 85%), mp=95-96° C.¹H-NMR (CDCl₃, 300 MHz): δ 2.37 (s, 6H, 2 CH3), 2.27 (m, 2H, CH₂CH₂NMe₂), 2.90 (m, 2H, CH₂CH ₂NMe₂), 6.86 (d, 1H, ³J=1.8 Hz, H-2), 7.03(d, 1H, ³J=8.8 Hz, H-7), 7.21 (dd, 1H, ⁴J=1.8 Hz, H-6), 7.70 (d, 1H,H-4), 9.36 (br s, 1H, H-1). ¹³C-NMR (CDCl₃, 75 MHz) δ 23.60(CH₂CH₂NMe₂), 45.47 (N(CH₃)₂), 60.25 (CH₂CH₂NMe₂), 112.42 (C-5), 112.98(C-7), 113.54 (C-3), 121.39 (C-4), 123.61 (C-2), 124.64 (C-6), 129.43(C-8), 135.36 (C-9).

NMR-data of the intermediate side-product2-(2-amino-5-bromo-phenyl)-4-dimethyl-amino-butan-1-ol, which is formedby ring opening/reduction: ¹H-NMR (CDCl₃, 300 MHz) δ 1.60-1.77,1.89-2.10 (2 m, 1H each, CH₂); 2.23 (s, 6H, N(CH₃)₂); 2.24-2.41 (m, 2H,CH₂NMe₂); 3.18-3.24 (m, 1H, CH₂OH); 3.24-3.34 (m, 1H, CH); 3.64-3.70 (m,1H, CH₂OH); 3.73 (br s, 1H, OH); 6.46 (d, 1H, 3J=8.2 Hz, Ar H-3); 7.08(dd, 1H, 4J=2 Hz, Ar H-4); 7.14 (1H, Ar H-6). ¹³C-NMR (CDCl₃, 75 MHz) δ32.33 (CH₂); 40.44 (CH); 45.72 (N(CH₃)₂); 53.88 CH₂NMe₂); 57.63 (CH₂OH);110.25 (Ar C-1); 110.89 (Ar C-3); 127.05, 130.83 (Ar C-4, C-6); 135.50(Ar C-5); 150.64 (Ar C-2).

Example 4 Preparation of[2-(1-Benzyl-5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine

In a 100 mL flask with inner thermometer and stirrer, 3.76 g (14.1 mmol)of [2-(5-bromo-1H.-indol-3-yl)-ethyl]-dimethyl-amine (Example 3) isdissolved in 40 mL of dry N,N-dimethyl formamide (DMF). To the solutionNaH (95%, 366 mg, 14.5 mmol) is added under an inert atmosphere.Hydrogen gas is forming, and the NaH dissolves under slight warmingduring about 30 minutes. The solution is then cooled to 5° C., and asolution of benzyl chloride (1.77 g, 14 mmol) in 10 mL of DMF is addeddropwise during a 10 minute period. The cooling bath is removed, and themixture is left stirring over night at ambient temperature. Then themixture is diluted with water (about 100 mL) and extracted withn-hexane/ether (about 1:1, 3×100 mL), and the combined organic extractsare re-extracted with water (3×100 mL). After drying and removal of thesolvent, the remaining oil is chromatographed on silica (80 g, 230-400mesh, ethyl acetate/ethanol 5:2+1% NH₃) to give 3.86 g (76.6%) of thetitle product as an oil which crystallized on standing, mp=54-55° C.¹H-NMR (CDCl₃, 300 MHz): δ 2.33 (s, 6H, N(CH₃)₂); 2.57-2.65, 2.86-2.94(2 m, 2H each, CH₂CH₂); 5.23 (s, 2H, CH₂Ph); 6.96 (s, 1H, H-2);7.05-7.08 (m, 2H, Ph-H) 7.14 (d, 1H, ³J=9 Hz, H-7); 7.22 (dd, 1H, ⁴J=2Hz, H-6); 7.25-7.33 (m, 3H, Ph-H); 7.74 (d, 1H, H-4). ¹³C-NMR (CDCl₃, 75MHz) δ 23.85 (CH₂); 45.77 (N(CH₃)₂); 50.31 (NCH₂); 60.55 (CH₂Ph);111.40, 112.58, 113.70, 121.90, 124.74, 126.91, 127.13, 127.93, 129.03,130.20 135.52, 137.50.

Example 5 Preparation of2-(1-Benzyl-5-bromo-1H-indol-3-yl)-N,N-dimethyl-acetamide

In a 200 mL flask with inner thermometer and stirrer, 9.43 g (33.5 mmol)of 2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 2) in 80 mLof dry DMF is dissolved. To the solution NaH (95%, 0.885 g mg, 35 mmol)is added under an inert atmosphere. Hydrogen gas is formed, and the NaHdissolves under slight warming. A solution of benzyl chloride (4.43 g,35 mmol) in 20 mL of DMF is added dropwise during a 10 minute period.There is again a slight exothermic reaction (45° C.), and a red-brownsolution formed., which is stirred at ambient temperature for another 4hours. The mixture is then poured into a vigorously stirredwater/TBME-emulsion (4:1 v:v), and stirring is continued for an hour.This leads to the crystallization of the product, which is filtered off,washed with TBME/MeOH (9:1, v:v), subsequently triturated with methanol(50 mL), filtered off, and washed with little methanol and TBME.Colourless crystals, 8.75 g, mp=50° C. From the mother liquors, a secondcrop of 1.2 g, mp=149.5-150° C. is obtained. The combined yield of thetitle product is 80%. ¹H-NMR (DMSO-D6, 300 MHz) δ 2.80, 3.00 (2 s, 3Heach, N(CH₃)₂); 3.73 (s, 2H, CH₂N); 5.36 (2H, CH₂Ph); 7.06-7.31 (m, 7H,5 Bn-H, H-6); 7.37 (d, 1H, J=8.8 Hz, H-7); 7.39 (s, 1H, H-2); 7.76 (d,1H, J=1.5 Hz, H-4). ¹³C-NMR (DMSO-D6, 75 MHz) δ 30.90 (CH₂N); 35.71,37.88 (N(CH₃)₂); 49.77 CH₂Ph); 108.92 (C); 112.18 (C); 112.77 (CH);122.38 (CH); 124.38 (CH): 127.67 Bn-(CH); 128.08 (CH); 129.22 (Bn-CH);129.66 (CH); 130.51 (C); 135.42 (C); 138.66 (C); 170.80 (CO).

Example 62-(3-Hydroxy-5-iodo-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

A 2 L flask with mechanical stirrer is charged with 5-iodo-isatin (78.1g, 0.286 mol), malonic acid (35.7 g, 0.343 mol), and pyridine (90.4 g,1.144 mol). The mixture is heated to 80° C. When most of the isatine hasdissolved, ethyl acetate (100 mL) is added to prevent blocking of thestirrer by the precipitating pyridinium(3-hydroxy-5-iodo-2-oxo-2,3-dihydro-1H-indol-3-yl)-acetate. After 1hour, precipitation of the latter salt starts, and when the mixture hasbeen kept stirring for another 2 hours, a suspension of the salt in anorange solution has formed. To this is added triethyl amine (43.3 g,0.429 mol), and the salt dissolves to give a dark solution. Then asolution of dimethyl carbamoyl chloride (40 g, 0.372 mol) in ethylacetate (50 mL) is added dropwise during 20 minutes. A solid starts toprecipitate, and the mixture is stirred for another 2 hours at 80° C.Then 4 N HCl is added (350 mL), and stirring is continued for 30additional minutes in order to hydrolyze any excess carbamoyl chloride.The mixture is then filtered, and the filter cake is washed with 50%ethanol and the with water. After drying 72.6 g (70.5%) of a grayishpowder of the title compound, mp.=246° C. ¹H-NMR (DMSO-D6, 300 MHz) δ2.62, 2.91 (2 s, 3 each, N(CH₃)₂); 2.91, 3.25 (AB, 2H, |²J|=16.4 Hz,CH₂); 5.97 (br s, 1H, OH); 6.59 (d, 1H, ³J=7.9 Hz, H-7); 7.46 (dd, 1H,⁴J=1.5 Hz, H-6); 7.54 (d, 1H, H-4); 10.15 (br s, 1H, NH). ¹³C-NMR(DMSO-D6, 75 MHz) δ 35.08, 37.48 (N(CH₃)₂); 40.86 (CH₂); 73.76 (C-3);84.29 (C-5); 112.49 (C-7); 132.44 (C-4); 136.06 (C-9); 137.72 (C-6);143.66 (C-8); 168.93 CONMe₂); 178.47 (C-2).

Example 7 Preparation of [2-(5-Iodo-1H-indol-3-yl)-ethyl]-dimethyl-amine

A 3 L flask is charged with2-(5-iodo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide(Example 6) (100 g, 0.277 mol), and 800 mL of DME. The suspension iscooled to −15° C., and sodium borohydride (31.5 g 96%, 0.832 mol) isadded to this mixture, which causes a raise of the temperature by 5° C.To this, BF₃-etherate is added dropwise during 30 minutes (157.6 g, 1.11mol). Initially there is a strong exothermic reaction (requires slowaddition of BF₃-etherate) and evolution of a gas. The temperature ismaintained between −15 and −10° C. during the addition. The formedorange slurry is then allowed to warm slowly to ambient temperature(25-27° C.), and left stirring over night (17 h). To this mixture, then4N NaOH (555 mL) is added and the mixture is heated under reflux for 50minutes. Then DABCO (34.3 g) is added, and refluxing the mixture iscontinued for two additional hours. Then water (250 mL) is added, andthe DME is removed on the rotavapor. The obtained orange slurry is thenextracted with TBME (1000 mL, 2×600 mL), and the combined organic layersare washed with water (800 mL) and brine (700 mL), and concentrated onthe rotavapor to about 600 mL. To the stirred residue, MnO₂ (72.4 g), isadded, and the exothermic oxidation causes a temperature rise of 20° C.Stirring is continued for one hour, and then the MnO₂ is filtered off.Removal of the solvent from the filtrate gives a brown oil, which isdissolved in toluene. The toluene is extracted for three times with 4 NHCl (300 mL, 2×150 mL). After adjustment of the pH of the combinedaqueous layers to about 10, the product is re-extracted with TBME (3×700mL). The combined organic layers are washed with water (500 mL), andbrine (500 mL), and after almost complete removal of the solvent on therotavapor and standing over night at 4° C. some of the productcrystallizes (39 g, 44.7%). Further concentration of the mother liquorsand standing for two additional days gives another crop of the titleproduct (9.5 g, 10.9%), while still about 20 g of material (about 22%)remains in the mother liquors. ¹H-NMR (CDCl₃, 300 MHz): δ 2.34 (s, 6H,NMe₂); 2.59-2.66 (m, 2H, CH₂NMe₂); 2.85-2.92 (m, 2H, ArCH₂); 6.90 (d,1H, ³J=2.2 Hz, H-2); 7.03 (d, 1H, ³J=8.4 Hz, H-7); 7.38 (dd, 1H, ⁴J=1.3Hz, H-6); 7.91 (d, 1H, H-4); 8.56 (br s, 1H, NH). ¹³C-NMR (CDCl₃-D6, 75MHz) δ 23.71 (ArCH₂); 45.65 (N(CH₃)₂); 60.32 (CH₂NMe₂); 82.77 (C-5);113.36 (C-6); 113.86 (C-3); 122.78 (C-2); 127.87 (C-4); 130.29 (C-7);130.33 (C-8); 135.62 (C-9).

Example 8 Preparation of[2-(1-Benzyl-5-iodo-1H-indol-3-yl)-ethyl]-dimethyl-amine

To a solution of [2-(5-iodo-1H-indol-3-yl)-ethyl]-dimethyl-amine(Example 7) (35.0 g, 111.4 mmol) in DMF (250 mL), sodium hydride isadded (2.81 g, 117 mmol) at RT in portions during 15 minutes. Themixture is then stirred for another 15 minutes, and then cooled to 4° C.A solution of benzyl chloride (14.1 g, 111.4 mmol) in DMF (50 mL) isadded during 20 minutes, and the temperature is maintained during 4 to8° C. The mixture is left stirring over night, and then most of thesolvent is removed on the rotavapor. To the residue is added water (500mL), and the product is extracted with TBME (2×250 mL). The organiclayer is washed with brine (2×250 mL), and after removal of the solvent,28.5 g of a brown oil is obtained. This is dissolved in ethyl acetate(500 mL) and the product is extracted with 4 N Hcl (550 mL). The productis liberated by adding 30% NaOH to the aqueous layer (300 mL), andre-extracted into ethyl acetate (500 mL). The organic layer is washedwith brine (2×250 mL), and the solvent removed to leave 20.2 g of abrown oil which is crystallized from di-isopropyl ether and pentane togive the title product (17.3 g, 38%). Concentrating the aqueous layer ofthe first gives a precipitate (18.8 g) which is recrystallized fromethyl acetate (250 to give 12.3 g of the N-benzyl ammonium chloride ofthe target.

Example 9 Preparation of2-(5-Iodo-1′-1H-indol-3-yl)-N,N-dimethyl-acetamide

To a suspension of2-(5-iodo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide(Example 6) (36.0 g, 0.1 mol) in DME (250 mL), at 20° C. borontrifluoride etherate (28.3 g, 0.2 mol) is added. Under cooling with anice bath, borane dimethyl sulfide complex (12.0 g, 0.15 mol) is addedduring 10 minutes, and then the cooling bath is removed. The temperaturerises slowly to 55° C., and a suspension forms at about 50° C. When theexothermic reaction has subsided, the mixture is stirred at 75° C. foranother 30 minutes, and then quenched by adding 4 N NaOH (100 mL). Themixture is heated under reflux for another 30 minutes, and then filteredwhile still hot. Removal of the solvent on the rotavapor leads tocrystallization of the product, which goes to completion on standing inthe refrigerator for 12 hours. The product is filtered off, washed withcold acetone (50 mL, −20° C.) and pentane, and dried to give the titleproduct (24.8 g, 75%) as crystals, mp.=195-200° C. ¹H-NMR (DMSO-D6, 300MHz) δ 2.80, 2.99 (2 s, 3H each, N(CH₃)₂); 3.69 (s, 2H, CH₂); 7.19 (d,1H, ³J=2.4 Hz, H-2); 7.21 (d, 1H, ³J=8.5 Hz, H-7); 7.32 (dd, 1H, ⁴J=1.7Hz, H-6); 7.92 (d, 1H, H-4); 11.04 (br s, 1H, NH). ¹³C-NMR (DMSO-D6, 75MHz) δ 31.11 (CH₂); 35.70, 37.91 (N(CH₃)₃); 82.82 (C-5); 108.54 (C-3);114.51 (C-7); 125.46 (C-2); 128.16 (C-4); 129.54 (C-6); 130.85 (C-9);135.91 (C-8).

Example 10 Preparation of2-(1-Benzyl-5-iodo-1H-indol-3-yl)-N,N-dimethyl-acetamide

To a solution of 2-(5-Iodo-1H-indol-3-yl)-N,N-dimethyl-acetamide (24.7g, 75.4 mmol) in DMF (90 mL), under an inert atmosphere sodium hydride(1.91 g 95%, 75.4 mmol) is added which leads to the formation of a paleyellow solution. When the evolution of hydrogen has ceased, benzylchloride (9.54 g, 75.4 mmol) is added in three portions over a period of10 minutes. The mixture warms to 60° C., and after stirring for one houra suspension forms. On the rotavapor, a part of the DMF (about 80 mL) isremoved, which leads to crystallization of the product. Water (300 mL)is added, and the crystallized product is triturated at 80° C. for onehour on the rotavapor. The product is filtered off, washed twice withwater (200 mL each washing), and dried to give 26.8 g (85%) of the titlecompound as pale yellow crystals, mp=167-168° C. From the mother liquor,another crop (2.6 g, 8%) is obtained which is also pure. ¹H-NMR(DMSO-D6, 300 MHz) δ 3.33, 3.72 (2 s, 3H each, N(CH₃)₂); 3.72 (s, 2H,CH₂CO); 5.34 (CH₂Ph); 7.08-7.15, 7.15-7.30 (2 m, 5H, Ph); 7.24 (d,³J=8.7 Hz, H-7); 7.26 (s, 1H, H-2); 7.32 (dd, ⁴J=1.3 Hz, H-6); 7.94 (d,1H, H-4). ¹³C-NMR (DMSO-D6, 75 MHz) δ 30.90 (CH₂CO); 35.72, 37.89(N(CH₃)₂); 49.70 (CH₂Ph); 83.31 (C-5); 108.61 (C-3); 113.26 (C-2);127.65 (2 Ph-C); 128.06 (C-6 or Ph C-4); 128.53 (C-4); 129.19 (Ph C-4 orC-6); 129.22 (2 Ph-C); 129.83 (C-7); 131.38 (Ph ipso-C); 135.79 (C-9);138.67 (C-8); 170.82 (CONMe₂).

Example 11 Preparation ofN,N-Dimethyl-2-(5-thiophen-2-yl-1H-indol-3-yl)-acetamide

A solution of 2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example2) (227 mg, 0.81 mmol) in DME (5 mL) is degassed by sparging with argonfor 10 minutes. Then thiophene-2-boronic acid (155 mg, 1.21 mmol),caesium carbonate (658 mg, 2.02 mmol), and π-allyltri-isopropylphosphino palladium bromide (15.7 mg, 0.04 mmol) are added,and the mixture is heated under reflux. Two additional portions ofcaesium carbonate (103 mg, 0.81 mmol) are added after 20 hours and 24hours to bring the reaction to completion. The black reaction mixture ispoured into 2 N NaOH (10 mL), and extracted twice with ethyl acetate.After removal of the solvent, the residue is chromatographed on silica(CHCl₃:MeOH 29:1 v:v) to give the title product (121 mg, 54%). ¹H-NMR(CDCl₃, 300 MHz) δ 2.96, 2.98 (2 s, 3H each, 2 CH₃); 3.77 (s, 2H, CH₂);6.84 (d, ³J=2.2 Hz, H-2); 7.06 (dd, ³J=5.0 Hz, ³J=3.6 Hz, thiopheneH-4); 7.21 (d, thiophene H-5); 7.21 (d, ³J=8.4 Hz, H-7); 7.25 (d,thiophene H-3); 7.40 (dd, ⁴J=1.8 Hz, H-6); 7.70 (d, H-4); 9.16 (br s,NH). ¹³C-NMR (CDCl₃, 75 MHz) δ 31.02 (CH₂); 36.00, 38.00 (2 CH₃); 109.05(C-3); 112.17 (C-7); 116.22 (C-4); 121.08 (C-6); 122.25 (thiophene C-3);123.70 (thiophene C-5); 124.31 (C-2); 126.29 (thiophene C-2); 127.83(C-9); 128.15 (thiophene C-4); 136.27 (C-8); 146.56 (C-5); 172.16 (CO).

Example 12 Preparation of{2-[5-(3-Benzyloxy-prop-1-ynyl)-1H-indol-3-yl]-ethyl}-dimethyl-amine

A Schlenk flask is charged with CuI (19 mg, 0.1 mmol), Pd(PhCN)₂Cl₂ (39mg, 0.1 mmol), piperidine (28 mL), and[2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Example 3) (2.70 g, 10mmol). The mixture is degassed, and then 0.4 mL of a solution of P(tBu)₃in hexane (0.2 mmol) is added. The stirred yellow solution is warmed to50° C., and a solution of benzyl propargyl ether (2.65 g, 20 mmol) inpiperidine (2 mL) is added during a 5 hour period. The yellow reactionmixture is left stirring for another 15 hours when HPLC indicatescomplete conversion of the 5-bromotryptamine. The mixture is dilutedwith ethyl acetate, washed with brine (4 times 10%, 3 times saturated),and dried. After removal of the solvent, the residue is triturated with20 mL hexane/O(i-Pr)₂ (1:1). The crystals which form are filtered off,washed with 4 mL of the same solvent mixture and dried in vacuo. Yieldof the title compound: 2.70 g (75%), mp.=93-95° C. ¹H-NMR (CDCl₃, 300MHz) δ 2.36 (5, 6, N(CH₃)₂); 2.63-2.70 (m, 2, CH₂NMe₂); 2.90-2.97 (m, 2,Indol-CH₂); 4.46 (s, 2, CH₂-alkin); 4.72 (s, 2, CH₂Ph); 6.94 (d, 1,J=2.2 Hz, H-2); 7.18 (dd, 1, J=8.4 Hz, J=0.7 Hz, H-7); 7.26 (dd, 1,J=1.4 Hz, H-6); 7.32, 7.37, 7.41 (m, 5, Ph p-, m-, o-H); 7.76 (d, 1,H-4); 8.63 (br s, 1, NH). ¹³C-NMR (CDCl₃, 75 MHz) δ 23.89 (indole-CH₂);45.73 (N(CH₃)₂); 58.55 (CH₂CC); 60.48 (CH₂NMe₂); 71.90 (CH₂Ph); 82.69(CH₂CC); 88.57 (CH₂CC); 111.45 (C-7); 113.15 (C-5); 114.64 (C-3); 122.90(C-2); 123.21 (C-4); 125.79 (C-6); 127.53 (C-9); 128.02, 128.40, 128.64(Ph p, m, o-C); 136.34 (C-8); 137.90 (Ph ipso-C).

Example 13 Preparation of3-(2-Dimethylamino-ethyl)-1H-indole-5-carbaldehyde

To a solution of [2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine(Example 3) (15 g, 56.1 mmol) in ether (450 mL), at −75° C. a solutionof tert-butyl lithium (99 ml of 1.7 N solution in hexanes, 168 mmol) isadded. The mixture is stirred for 50 minutes at −75° C., and then for 30minutes at −30° C. To the obtained beige suspension, DMF (22.5 ml) isadded during 15 minutes, and then the mixture is allowed to warm toambient temperature. The mixture is poured on water and extracted withdiethyl ether (500 mL). After washing the organic layer with brine (3times 500 mL), and drying (sodium sulfate), removal of the solventleaves the crude aldehyde, which is recrystallized, from toluene/hexane.Yield of the title compound: 9.9 g (81.8%) yellowish plates, mp=103° C.¹H-NMR (CDCl₃, 300 MHz) δ 2.36 (s, 6H, N(CH₃)₂); 2.65-2.75 (m, 2H, CH₂);2.96-3.03 (m, 2H, CH₂NMe₂); 7.08 (d, 1H, 3J=2.7 Hz, H-2); 7.33 (d, 1H,³J=8.4 Hz, H-7); 7.70 (dd, 1H, ⁴J=1.7 Hz, H-6); 8.13 (d, 1H, H-4); 8.74(br s, 1H, NH); 10.02 (s, 1H, CHO). ¹³C-NMR (CDCl₃, 75 MHz) δ 23.91(CH₂); 45.76 (CH₃); 60.40 (CH₂N); 111.85 (C-7); 116.68 (C-3); 122.87(C-6); 123.61 (C-2); 124.04 (C-4); 127.68 (C-9); 129.35 (C-5); 140.06(C-8); 192.56 (CHO).

Example 14 Preparation ofDimethyl-[2-(5-vinyl-1H-indol-3-yl)-ethyl]-amine

To a solution of 3-(2-dimethylamino-ethyl)-1H-indole-5-carbaldehyde(Example 13) (0.216 g, 1 mmol) in THF (5 mL), methyl triphenylphosphonium bromide (0.393 g, 1.1 mmol) is added. To the obtainedslurry, under an argon atmosphere potassium tert-butoxide (0.118 g, 1.05mmol) is added in three portions at ambient temperature. When thin layerchromatography (TLC) indicates complete conversion of the aldehyde, themixture is poured on ice and extracted with ethyl acetate. Removal ofthe solvent gives a residue which is chromatographed on silica (25 g,CHCl₃, MeOH, NEt₃ 19:1:0.5 v:v:v) to give the title product as paleyellow oil (0.190 g, 88%). ¹H-NMR (CDCl₃, 300 MHz) δ 2.37 (s, 6H,N(CH₃)₂); 2.64-2.70 (m, 2H, CH₂NMe₂); 2.92-2.99 (m, 2H, CH₂); 5.13 (d,1H, J=10.9 Hz, cis H₂C═CH); 5.69 (d, 1H, J=17.6 Hz, trans H₂C═CH); 6.84(dd, 1H, H₂C═CH); 6.94 (br s, 1H, H-2); 7.24 (d, 1H, J=8.2 Hz, H-7);7.31 (dd, J=1.8 Hz, H-6); 7.58 (d, 1H, H-4); 8.66 (br s, 1H, NH).¹³C-NMR (CDCl₃, 75 MHz) δ 24.00 (CH₂); 45.73 (N(CH₃)₂); 60.62 (CH₂NMe₂);110.93 (H₂C═CH); 111.50 (C-7); 114.66 (C-3); 117.41 (C-4); 120.20 (C-6);122.42 (C-2); 127.83 (C-5); 129.34 (C-9); 136.45 (C-8); 138.22 (H₂C═CH).

Example 15 Preparation of[3-(2-Dimethylamino-ethyl)-1H-indol-5-yl]-methanol

A 50 ml hydrogenation bomb is charged with3-(2-dimethylamino-ethyl)-1H-indole-5-carbaldehyde (Example 13) (1.0 g,4.62 mmol) and methanol (10 mL). The bomb is purged with hydrogen (threetimes to 200 psi and release to atmospheric pressure), and thenpressurised to 200 psi. After stirring for one hour, the pressure isreleased, and a solution of [Rh DiPFc (COD)]BF₄ (6.6 mg, S/C=500) inmethanol (1 ml) is added through a septum port. The bomb is pressurizedwith hydrogen to 200 psi, and left stirring at ambient temperature for18 hours. Removal of the solvent from the hydrogenation mixture givesthe title product (1.05 g, quant.) as an oil.

¹H-NMR (CDCl₃, 300 MHz) δ 2.21 (s, 6H, N(CH₃)₂); 2.49-2.60 (m, 2H,CH₂NMe₂); 2.73-2.83 (m, 2H, CH₂CH₂NMe₂); 4.63 (s, 2H, CH₂OH); 4.85 (brs, 1H, OH); 6.76 (s, 1H, H-2); 7.03 (dd, 1H, ³J=8.2 Hz, ⁴J=1.5 Hz, H-6);7.14 (d, 1H, H-7); 7.41 (d, 1H, H-4); 8.96 (br s, 1H, NH). ¹³C-NMR(CDCl₃, 75 MHz) δ 22.99 (CH₂); 44.73 (CH₃); 59.71 (CH₂N); 66.11 (CH₂OH);111.62 (C-7); 113.07 (C-3); 117.62 (C-4); 122.01 (C-6); 122.67 (C-2);127.48 (C-9); 132.38 (C-5); 136.15 (C-8)

Example 16 Preparation of3-Dimethyl-carbamoylmethyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carboxylicacid ethyl ester

A pressure vessel is charged with2-(5-Bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide(21.92 g, 70 mmol), Pd(dppp)Cl2 (4.13 g, 7 mmol), triethyl amine (28.4g, 0.28 mol) and ethanol (405 ml, solvent). After assembling and purgingwith nitrogen, the vessel is charged with carbon monoxide to a pressureof 20 bar, and the carbonylation is performed at 120° C. over night. Thereaction mixture is filtered through a celite pad, and the solvent isremoved on the rotavapor. The residue is kept under reflux with ethylacetate (750 mL), and filtered. After washing the filter cake for threetimes with ethyl acetate (3*100 mL), the filtrate is concentrated (toca. 300 mL), and the obtained suspension is left at 0° C. over night.The product is filtered off and dried to give 19.0 g (87%) of the titlecompound in the form of beige crystals. ¹H-NMR (CDCl₃, 300 MHz) δ 1.29(tr. 3H, J=7.0 Hz); 2.62, 2.94 (2 s, 3 each, N(CH₃)₂); 2.98, 3.32 (AB,2J=18.2 Hz, CH₂NMe₂); 417-4.34 (m, 2H, CH₂Me); 6.02 (s, 1H, OH); 6.82(d, 1H, J=7.6 Hz, H-7); 7.79 (br s, 1H, H-4); 7.81 (dd, 1H, J=7.6 Hz,J=1.8 Hz, H-6). ¹³C-NMR (CDCl₃, 75 MHz) □ 15.16 (CH₃); 35.13, 37.56(N(CH₃)₂); 46.49 (CH₂NMe₂); 61.02 (CH₂Me); 73.56 (C-3); 109.75 (C-7);123.16, 124.73 (C-6); 131.72 (C-4); 133.49, 148.53 (C-8); 166.34,168.78, 179.23 (3 C═O).

Example 17 Preparation of3-(2-dimethylamino-ethyl)-1H-indole-5-carbonitrile

Under an inert atmosphere a flask is charged with[2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Example 3) (1.0 g,3.74 mmol), zink cyanide (0.235 g, 2 mmol), Pd₂(dba)₃xCHCl₃ (0.194 mg, 5mol %), dppf (bis-diphenylphosphino ferrrocene) (0.207 g, 0.374 mmol, 10mol %), and DMF (12 mL). The orange slurry is heated to 110° C. andstirred for 21 hours. To the black suspension which has formed, THF (100mL) is added, and this is extracted with 1 N NaOH (100 mL). The organiclayer is washed with water twice (50 mL each), dried and removal of thesolvent gives the title product (0.67 g, 84%) as brown solid.

¹H-NMR (CDCl₃, 300 MHz) δ 2.35 (s, 6H, 2 CH₃); 2.67 (m, 2H, CH₂NMe₂);2.91 (m, 2H, CH₂); 7.01 (s, 1H, H-2); 7.13 (d, 1H, ³J=8.3 Hz, H-7); 7.26(dd, 1H, ⁴J=1.6 Hz, H-6); 7.87 (d, 1H, H-4); 9.80 (br s, 1H, NH).¹³C-NMR (CDCl₃, 75 MHz) δ 23.48 (CH₂); 45.42 (CH₃); 60.06 (CH₂N); 101.75(C-5); 112.24 (C-7); 114.74 (C-3); 121.41 (CN); 124.49 (C-4); 124.62(C-6); 124.75 (C-2); 127.31 (C-9); 138.47 (C-8).

Example 18 Preparation of2-(1-Benzyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

A 500 mL flask is charged with N-benzyl isatin (55 g, 0.231 mol),malonic acid (28.95 g, 0.278 mol), and pyridine (73.4 g, 0.927 mol). Tothe formed red suspension, ethyl acetate (50 mL) is added, and thestirred mixture is heated to 80° C. After about 30 minutes a solutionhas formed which is kept stirring at 80° C. until no further formationof carbon dioxide is observed (about 2.5 h). Then triethyl amine (35.2g, 0.347 mol) is added, and the mixture is stirred for another 10minutes at 80° C. To the dark red solution, then dropwise (exothermicl)dimethyl carbamoyl chloride (32.4 g, 0.301 mol) is added during 10minutes. When the evolution of carbon dioxide ceases, the mixture iskept stirring at 80° C. for another two hours, and then the solvent isremoved from the brown suspension on the rotavapor. To the residue, HCl(4N, 0.2 L) is added, and the formed suspension is stirred for one hourat 80° C. After cooling and standing in the refrigerator over night, thecrystals are filtered off, washed twice with water (about 150 mL eachwash) and dried in vacuo to give light brown crystals. Yield of thetitle compound: 66.7 g (88.7% based on N-benzyl isatin). ¹H-NMR (CDCl₃,300 MHz) δ 2.69, 3.03 (AB, 2H, ²J=16.1Hz, CH₂CONMe₂); 2.91, 2.99 (2 s, 3each, N(CH₃)₂); 4.87, 4.89 (AB, 2H, ²J=15.8 Hz, CH₂Ph); 6.70 (d, 1H,J=7.7 Hz, H-7); 7.01 (dtr, J=7.7 Hz, J=1.1Hz, H-5); 7.17 (dtr, 1H, J=7.7Hz, J=1.1Hz, H-6); 7.21-7.34 (m, 5H, Ph); 7.49 (dd, J=7.3 Hz, J=1.8 Hz,H-4). ¹³C-NMR (CDCl₃, 75 MHz) δ 35.64, 37.66 N(CH₃)₂; 38.21 (CH₂CONMe₂);44.02 (CH₂Ph); 74.61 (C-3); 109.70 (C-7); 123.38 (C-5); 124.63 (C-4);127.51, 127.90, 129.03 (Ph ortho-C, para-C, meta-C); 129.82 (C-6),131.15 (C-9); 135.77 (Ph ipso-C); 142.47 (C-8); 171.18 (CONMe₂); 176.51(C-2).

Example 19 Preparation of2-(1-Benzyl-2-oxo-1,2-dihydro-indol-3-ylidene)-N,N-dimethyl-acetamide

A mixture of2-(1-benzyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide(Example 21) (1.0 g, 3.08 mmol), acetic acid (8 mL) and acetic anhydride(2 mL) is heated under reflux for two hours, and then poured in water(100 ml). Extraction with CHCl₃ gives 1.2 g of a yellow oil which ischromatographed on silica gel (ethyl acetate:hexanes 1:1 v:v) to givethe E-stereoisomer (333 mg, less polar) of the title compound and itsZ-stereoisomer (110 mg).

(E)-stereoisomer (kinetic product, major): ¹H-NMR (CDCl₃, 300 MHz) δ3.11, 3.13 (2 s, 3 each, N(CH₃)₂); 4.94 (s, 2, CH₂Ph); 6.67 (d, 1, J=7.9Hz, H-7); 6.96 (“dtr”, 1, J=7.6 Hz, J=0.9 Hz, H-5); 7.18 (“dtr”, 1,J=7.8 Hz, J=1.2 Hz, H-6); 7.23, 7.29 (m, 5, Ph-H); 7.27 (s, 1,CHC(O)NMe₂); 7.81 (“dd”, 1, J=7.8 Hz, J=0.9 Hz, H-4). ¹³C-NMR (CDCl₃, 75MHz) δ 35.27, 37.97 (N(CH₃)₂); 44.16 (CH₂Ph); 109.40 (C-7); 120.28(C-9); 122.92 (C-5); 125.98 (C-4); 126.02 (CHCONMe₂); 127.47 (Ph-orthoC); 127.87 (Ph para-C); 128.98 (Ph meta-C); 131.31 (C-6); 132.72 (C-3);135.79 (C-15); 144.15 (C-8); 166.08 (C-2); 167.79 (CONMe₂);(Z)-stereoisomer (thermodynamic product): ¹H-NMR (CDCl₃, 300 MHz) δ3.07, 3.14 (2s, 3 each, N(CH₃)₂); 4.90 (s, 2, CH₂Ph); 6.68 (d, 1, J=7.9Hz, H-7); 6.91 (s, 1, CHC(O)NMe₂); 7.00 (“dtr”, 1, J=7.5 Hz, J=0.9 Hz,H-5); 7.19 (“dtr”, J=7.8 Hz, J=0.9 Hz, H-6); 7.25-7.35 (m, 5 Ph-H); 7.43(“dd”, J=7.4 Hz, J=0.6 Hz, H-4). ¹³C-NMR (CDCl₃, 75 MHz) δ 34.78, 37.66(N(CH₃)₂); 43.94 (CH₂Ph); 109.59 (C-7); 120.96 (C-4); 121.63 (C-9);122.52 (C-5); 126.73 (CHCONMe₂); 127.56 (Ph-ortho C); 127.85 (Phpara-C); 128.96 (Ph meta-C); 130.70 (C-6); 129.67 (C-3); 135.84 (C-15);143.22 (C-8); 165.56 (C-2); 166.51 (CONMe₂).

Example 20 Preparation of2-(1-Benzyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

A flask is charged with2-(1-benzyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide(Example 19) (10.0 g, 30.8 mmol), acetic acid (250 mL), acetic anhydride(100 g), and Zn-dust (20 g). The mixture is kept under reflux, until allof the starting material is consumed (3 h). The solids are then filteredoff, and from the filtrate the solvent is removed to leave an oil whichcrystallizes to a pale brown solid on treatment with di-iso-propylether. Yield of the title compound: 9.2 g (96.8%). ¹H-NMR (CDCl₃, 300MHz) δ 2.73 (dd, 1, ²J=16.5 Hz, J=9.4 Hz, CH₂NMe₂); 3.00, 3.01 (2 s, 6,N(CH₃)₂); 3.20 (dd, 1, J=3.2 Hz, CH₂NMe₂); 4.06 (dd, 1, H-3); 4.90, 4.97(AB, 2, ₂J=15.6 Hz, CH₂N); 6.70 (d, 1, J=7.9 Hz, H-7); 6.97 (“dtr”,J=7.5 Hz, J=1.2 Hz, H-5); 7.13 (“dtr”, J=7.8 Hz, J=1.2 Hz, H-6);7.22-7.29, 7.29-7.33 (m, 5, 5 Ph-H); 7.38 (br d, 1, J=7.5 Hz, H-4).¹³C-NMR (CDCl₃, 75 MHz) δ 35.25 (CH₂NMe₂); 36.07, 37.51 (N(CH₃)₂); 42.59(C-3); 44.28 (NCH₂Ph); 109.12 (C-7); 122.66 (C-5); 124.85 (C-4); 127.49(Ph meta-C); 127.71 (Ph para-C); 128.04 (C-6); 128.92 (Ph ortho-C);129.63 (C-9); 136.19 (Ph ipso-C); 143.52 (C-8); 170.00 (CONMe₂); 178.02(C-2),

Example 21 Preparation of2-(1-Benzyl-5-chloro-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

A flask is charged with2-(1-benzyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide(Example 18) (10 g, 30.83 mmol), N-chloro succinimide (NCS) (4.12 g,30.83 mmol), acetic acid (40 and toluene (20 mL). The orange suspensionis then stirred over night and becomes a homogeneous solution. After theaddition of about 5 mL of water, the solvent is removed on therotavapor. To the residue, water is added, and the product is extractedwith chloroform. After drying and removal of solvent 11 g of crudeproduct is obtained which after chromatography on silica (toluene:ethylacetate 1:1) gives the title product (9.76 g, 88%) as yellow foam.¹H-NMR (CDCl₃, 300 MHz) δ 2.74, 3.08 (AB, 2H, ²J=16.3 Hz, CH₂CONMe₂);4.85 (s, 2H, NCH₂Ph); 6.32 (br s, 1H, OH); 6.58 (d, 1H, ³J=8.2 Hz, H-7);7.10 (dd, 1H, 4J=2.0 Hz, H-6); 7.13-7.32 (m, 5H, Ph); 7.46 (d, 1H, H-4).¹³C-NMR (CDCl₃, 75 MHz) δ 35.77, 37.77 (N(CH₃)₂); 38.80 (CH₂CONMe₂);44.27 (CH₂Ph); 74.65 (C-3); 110.72 (C-7); 125.10 (C-4); 127.33 (Phortho-C); 127.90 (Ph para-C); 128.54 (C-5); 129.00 (Ph meta-C); 129.49(C-6); 132.80 (C-9); 135.26 (C-15); 141.08 (C-8); 170.31 (C-11); 175.96(C-2).

Example 22 Preparation of Acetic acid1-benzyl-3-dimethyl-carbamoylmethyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-5-ylmethylester

A 4 L flask is charged with para-formaldehyde (92.6 g, 3.082 mol),glacial acetic acid (400 mL), and sulfuric acid (60.5 g, 0.617 mol). Themixture is heated at 90° C. until a homogeneous solution forms. To this,during 90 minutes a solution of2-(1-benzyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide(Example 18) (200 g, 0.617 mol) in acetic acid (1000 mL) and water (22.2mL) is added. The mixture is kept at 90° C. for another 30 minutes,until all of the starting material is consumed (HPLC). The reaction isthen quenched by the addition of sodium acetate (50.5 g), and thesolvent is removed on the rotavapor. The remaining red oil is stirredwith water (1000 mL), and this mixture is extracted with chloroform(2×500 mL). After drying the combined organic layers and removal of thesolvent, the title product is obtained as a red foam (220 g, 90%). Thismaterial contains about 35% of by-products, the main one (about 30%)being the diaryl methane, and products formed by elimination of the 3-OHgroup. HPLC-conditions: column 12.5 m C18 modified, flow: 1 mL/min,gradient 25% acetonitrile/75% water to 100% acetonitrile in 10 minutes,then another 3 minutes acetonitrile. Detection at 254/210 nm. Retentiontimes: 5-hydroxymethylated product: 3.91 min; starting material 5.40min; 5-acetoxymethyl title product: 5.65 min; 6.4-7.3 min:diphenylmethane derivatives and isatylidenes. ¹H-NMR (CDCl₃, 300 MHz) δ2.06 (s, 3, CH₃CO); 2.71, 3.05 (AB, 2, J=16.1Hz, CH₂CO); 2.93, 3.02 (2s, 3 each, N(CH₃)₂); 4.87, 4.90 (AB, 2, J=15.6 Hz, CH₂N); 5.00 (s, 2,CH₂OAc); 6.43 (s, 1, OH); 6.68 (d, 1, J=7.9 Hz, H-7); 7.18 (dd, 1, J=8.2Hz, J=1.8 Hz, H-6); 7.23-7.33 (m, 5H, 5 Ph-H); 7.50 (d, J=1.8 Hz, 1,H-4). ¹³C-NMR (CDCl₃, 75 MHz) δ 21.38 (CH₃COO); 35.78, 37.78 (N(CH₃)₂);38.31 (CH₂CO); 44.22 (NCH₂); 66.46 (CH₂OAc); 74.60 (C-3); 109.62 (C-7);125.15 (C-4); 127.47 (Bn meta C); 127.62 (Bn para-C); 129.01 (Bnortho-C); 130.31 (C-6); 131.05 (C-5); 131.47 (C-9); 135.56 (Bn ipso-C);142.56 (C-8); 170.89, 170.90 (CH₃COO, CONMe₂); 176.33 (C-2).

Example 23 Preparation of2-(1-Benzyl-3-hydroxy-5-hydroxy-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

To a solution of acetic acid with1-benzyl-3-dimethyl-carbamoylmethyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-5-ylmethylester (Example 22) (18.3 g, 46.2 mmol) in methanol (400 mL), potassiumcarbonate (20 g) is added, and the mixture is kept under reflux for 16hours (no starting material by HPLC). The mixture is then neutralizedwith 2 N sulfuric acid, and the methanol is removed on the rotavapor.The remaining aqueous phase is extracted with chloroform (2×200 mL), thecombined extracts are washed with water (2×200 mL), dried and afterremoval of the solvent the title product is obtained as light brown foam(16.8 g, quantitative). ¹H-NMR (CDCl₃, 300 MHz) δ 2.74, 3.03 (AB, 2,²J=15.8 Hz, CH₂CONMe₂); 2.86, 2.91 (2 s, 3 each, N(CH₃)₂); 4.52 (s, 2,CH₂OH); 4.84, 4.86 (AB, 2, ²J=15.8 Hz, NCH₂); 6.62 (d, 1, ³J=7.9 Hz,H-7); 7.11 (dd, 1, ⁴J=1.5 Hz, H-6); 7.21-7.26 (m, 5, Ph); 7.47 (d, 1,H-4). ¹³C-NMR (CDCl₃, 75 MHz) δ 35.74, 37.78 (N(CH₃)₂); 38.74(CH₂CONMe₂); 44.16 (NCH₂); 65.08 (CH₂OH); 74.61 (C-3); 109.56 (C-7);123.71 (C-4); 127.43 (Bn ortho-C); 127.81 (Bn para-C); 128.70 (C-6);128.96 (Bn meta-C); 131.27 (C-9); 135.73 (Bn ipso-C); 136.37 (C-5);141.91 (C-8); 170.66 (C-11); 176.69 (C-2).

Example 24 Preparation of2-(1-Benzyl-5-formyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

Under inert atmosphere, a flask is charged with manganese dioxide (8.7g, 0.1 mop and2-(1-benzyl-3-hydroxy-5-hydroxy-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide(Example 23) (3.54 g, 0.01 mol). To this, mol sieve (4 A, 2 g) anddichloromethane (100 mL) are added, and the mixture is heated underreflux for six hours. The mixture is then filtered, and evaporation ofthe solvent leaves 3.5 g of a dark brown foam. This is chromatographedon silica (ethyl acetate) to give 1.8 g (50%) of the title product aspale yellow foam. ¹H-NMR (CDCl₃, 300 MHz) δ 2.82, 3.13 (AB, 2H,²J=16.1Hz, CH₂NMe₂); 2.95, 2.98 (2 s, 3H each, N(CH₃)₂); 4.93, 4.94 (AB,2H, ²J=16 Hz, NCH₂Ph); 6.11 (s, 1H, OH); 6.82 (d, 1H, ³J=7.9 Hz, H-7);7.23-7.38 (m, 5H, Ph); 7.72 (dd, 1H, ⁴J=1.5 Hz, H-6); 8.00 (d, 1H, H-4);9.83 (s, 1H, CHO). ¹³C-NMR (CDCl₃, 75 MHz) δ 35.76, 37.70 (N(CH₃)₂);38.72 (CH₂CONMe₂); 44.42 (NCH₂Ph); 74.06 (C-3); 109.80 (C-7); 125.38(C-4); 127.42 (Bn ortho-C); 128.14 (Bn para-C); 129.16 (Bn meta-C);132.00, 132.31 (C-5, C-9); 133.49 (C-6); 135.04 (Ph ipso-C); 148.24(C-8); 170.22 (CONMe₂); 176.69 (C-2); 190.80 (CHO).

Example 25 Preparation of 1-Allyl-1H-indole-2,3-dione

A 500 mL flask is charged with isatin (50 g, 339 mmol), allyl chloride(33.8 g, 441 mmol), potassium carbonate (93.9 g, 679 mmol), and DMF (100mL). The mixture is stirred at 70° C. for 14 hours (complete conversionby TLC), and then diluted with DMF. After filtration over a pad ofcellite and removal of the solvent, the product remained as red crystals(68 g) which are used directly in the next step. ¹HNMR (CDCl₃, 300 MHz)δ 4.34 (dtr, 1H, ³J=5.3 Hz, ⁴J=1.8 Hz, NCH₂CHC═CH₂); 5.27 (dm, 1H,³J=10.3 Hz, NCH₂CHC═CH_(cis)); 5.30 (dm, 1H, ³J=17.0 Hz,NCH₂CHC═CH_(trans)); 5.82 (ddtr, NCH₂CHC═CH₂); 6.87 (d, 1H, 3J=7.9 Hz,H-7); 7.09 (br tr, 1H, ³J=7.3 Hz, H-5); 7.55 (dtr, 1H, ³J=8 Hz, H-6);7.57 (d m, 1H, ³J=7.3 Hz, H-4). ¹³C-NMR (CDCl₃, 75 MHz) δ 42.82 (NCH₂);111.11 (C-7); 117.77 (C-9); 118.80 (CH═CH₂); 123.96 (C-5); 125.50 (C-4);130.51 (CH═CH₂); 138.48 (C-6); 150.96 (C-8); 158.02 (C-2); 183.29 (C-3).

Example 26 Preparation of2-(1-Allyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

A 1 L flask is charged with 1-allyl-1H-indole-2,3-dione (Example 25)(63.6 g, 339 mmol), and pyridine (107.5 g, 1.36 mol). To this, malonicacid (42.4 g, 407 mmol) is added, which leads to a slight exothermicreaction. The obtained slurry is heated at 80° C. until the formation ofcarbon dioxide ceases and TLC indicates no starting material to bepresent. To the reddish solution, triethyl amine (51.6 g, 441 mmol) isadded, and the mixture is stirred for another 10 minutes when a dark redsolution forms. To this solution, dimethyl carbamoyl chloride (47.5 g,441 mmol) is added during 15 minutes which gives an exothermic reactionwith vigorous formation of carbon dioxide. The mixture is stirred foranother 15 minutes, and then the solvent is removed on the rotavapor. Tothe residue, water (about 300 mL) and chloroform (about 300 mL) areadded. The pH is adjusted to slightly acidic (6.0) by adding 2 N HCl.The organic layer is separated off, and the aqueous layer extracted oncemore with chloroform (100 mL). The combined organic layers are dried(sodium sulfate), filtered and, after removal of the solvent, a lightbrown solid is obtained (107 g). This is triturated with cold water (500mL, 4° C.), and filtered. After washing and drying the title product isobtained as beige crystals (76.6 g, 82%). ¹HNMR (DMSO, 300 MHz) δ 2.63,2.94 (2 s, 3H each, N(CH₃)₂); 3.04, 3.30 (AB, 2H, ²J=16.4 Hz,CH₂CONMe₂); 4.28, 4.35 (ABdtr, 2H, ²J=16.3 Hz, NCH₂CH═CH₂); 5.15 (ddtr,1H, ²J=1.5 Hz, ³J=10.3 Hz, ⁴J=1.5 Hz, CH₂CH═CH_(cis)); 5.38 (ddtr, 1H,³J=17.3 Hz, ⁴J=1.8 Hz, CH₂CH═CH_(trans)); 5.84 (ddtr, 1H, 3J=4.7 Hz,CH₂CH═CH₂); 6.82 (d, 1H, J=7.6 Hz, H-7); 6.95 (dtr, 1H, ³J=7.6 Hz,⁴J=1.2 Hz, H-5); 7.21 (dtr, 1H, ³J=7.6 Hz, ⁴J=1.5 Hz, H-6); 7.32 (dd,1H, ³J=7.3 Hz, ⁴J=1.2 Hz, H-4). ¹³C-NMR (DMSO, 75 MHz) δ 35.22, 37.67(N(CH₃)₂); 41.23 (CH₂CONMe₂); 42.27 (NCH₂CH═CH₂); 73.69 (C-3); 109.36(C-7); 117.34 (NCH₂CH═CH₂); 122.22 (C-5); 123.66 (C-4); 129.29 (C-6);132.39 (C-9); 132.75 (NCH₂CH═CH₂); 144.30 (C-8); 168.79 (CONMe₂); 177.13(C-2).

Example 27 Preparation of2-(1-Allyl-3-hydroxy-5-hydroxy-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

To a suspension of para-formaldehyde (36.2 g, 1.13 mol) in 150 ml ofglacial acetic acid, sulfuric acid (22.2 g, 0.226 mol) is added and themixture heated at 80° C., until a clear solution has been formed. Tothis, during 45 minutes a solution of2-(1-allyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide(example 26) (62 g, 226 mmol) in a mixture of glacial acetic acid (350mL) and water (10 mL) is added.

The red reaction mixture is stirred for another hour at 80° C., and bythen all of the starting material is consumed (HPLC). Sodium acetate(46.3 g, 564 mmol) is added, and after stirring for 5 minutes an orangesuspension forms. The solvent is removed on the rotavapor, and to theresidue water (about 250 mL) is added. Extraction with chloroform (2×200mL), drying the organic layer and removal of the solvent leaves thecrude title product (77.7 g, quant.) as a red oil. After chromatographicpurification white crystals, mp=125° C. ¹H-NMR (CDCl₃, 300 MHz) δ2.71,2.94 (AB, 2H, ²J=16.1Hz, CH₂CONMe₂); 2.83, 2.84 (2 s, 3H each, N(CH₃)₂);4.19, 4.25 (AB_(Allyl), 2H, ²J=16.4 Hz, ³J=5.3 Hz, NCH₂); 4.47 (s, 2H,CH₂OH); 5.12 (dd, 1H, ²J=1.2 Hz, ³J=10.3 Hz, cis CH═CH₂), 5.51 (dd, 1H,³J=17.3 Hz, trans CH═CH₂); 5.75 (ddtr, 1H, CH═CH₂); 6.21 (br s, 1H, OH);6.70 (d, 1H, ³J=7.9 Hz, H-7); 7.15 (dd, 1H, ⁴J=1.5 Hz, H-6); 7.37 (d,1H, H-4). ¹³C-NMR (CDCl₃, 75 MHz) δ 35.71, 37.84 (N(CH₃)₂); 38.87(CH₂CONMe₂); 42.67 (NCH₂); 64.80 (CH₂OH); 74.46 (C-3); 109.36 (C-7);117.73 (CH═CH₂); 123.43 (C-4); 128.63 (C-6); 131.00 (C-9); 131.33(CH═CH₂); 136.35 (C-5); 141.89 (C-8); 170.53 (C-11); 176.36 (C-2),

Example 28 Preparation of1-benzyl-1H-spiro[indole-3,3′-oxolano]-2,5′-dione

A solution of2-(1-Benzyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide(1.54 g, 8 mmol) and formaldehyde (2.02 g 37% solution in water, 40mmol) in acetonitrile (5 ml) is heated at reflux over the weekend. Afterremoval of the solvents, the residue is chromatographed on silica(toluene:ethyl acetate 2:1 v:v) to give the product as a pale yellowsolid. ¹H-NMR (CDCl₃, 300 MHz) δ 2.73, 3.17 (AB, ²J=18 Hz, CH₂O); 4.38,4.63 (AB, ²J=9 Hz, CH₂CO); 4.92 (s, 2H, CH₂Ph); 6.82 (d, 1H, J=7.4 Hz,Ar ortho-H), 7.08 (tr, 1H, Ar—H); 7.20-7.35 (m, 7H, Ar H). ¹³C-NMR(CDCl₃, 75 MHz) δ 38.82 (CH₂O); 44.58 (CH₂CO); 50.58 (q C); 75.07(CH₂Ph); 110.04, 122.64, 123.89 (3 Ar—CH), 127.54 (2 C, Ph CH); 128.16(Ar CH); 129.16 (2 C, Ph CH); 129.64 (Ar CH); 130.77, 135.40, 142.18 (3Ar C); 171.37, 175.91 (2 C═O).

Example 29 Preparation ofDimethyl-{2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-1H-indol-3-yl]ethyl}-amine

A solution of [2-(5-Bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (1.069 g,4 mmol) in dried diethyl ether (25 ml) is prepared under rigorousexclusion of moisture and oxygen. The solution is cooled to −78° C., andthen a solution of t-BuLi (8.0 ml 1.5 N in pentanes, 12 mmol) is addedslowly over 10 minutes. A beige suspension is formed, which is stirredat −78° C. for another 15 minutes, and then allowed to warm over 30minutes to −30° C. The mixture is stirred at −30° C. for another 30minutes, and then a solution of2-isopropoxy-4,4,5,5,-tetramethyl-[1,3,2]dioxaborolane (1.116 g, 6 mmol)in ether (5 mL) is added dropwise within 10 minutes whilst thetemperature is maintained in the range between −30 to −25° C. Thereaction mixture is stirred for another 30 minutes at −30° C. and thenallowed to warm to ambient temperature. After stirring for another 90minutes, the reaction is quenched by the addition of water (15 ml) andchloroform (30 ml). The organic layer is separated, and washed withbrine (15 ml). The aqueous layer is washed with chloroform (15 ml), andfrom the combined organic layers the solvent is removed on the rotavaporto leave a brown oil (1.5 g) which is chromatographed on silica(CHCl₃:MeOH 19:1 v:v) to give the product as an oil (0.193 g, 15.3%).¹H-NMR (CDCl₃, 300 MHz): δ 1.37 (s, 12H, 4 CH₃); 2.36 (s, 6H, N(CH₃)₂);2.66-2.74 (m, 2H, CH₂NMe₂); 2.93-3.02 (m, 2H, CH₂); 6.94 (d, J=2.1Hz,H-2); 7.30 (dd, 1H, J=8.3 Hz, J=0.7 Hz, H-7); 7.60 (dd, 1H, J=8.1 Hz,J=1.0 Hz, H-6 (NOE with 4 CH₃)); 8.09 (s, 1H, H-4 (NOE with 4 CH₃));8.94 (br s, 1 NH). ¹³C-NMR (CDCl₃, 75 MHz) δ 23.43 (ArCH₂); 25.02 (4CH₃); 45.33 (N(CH₃)₂); 60.15 (CH₂NMe₂); 83.70 (C(Me)₂); 110.86 (C-7);114.30 (C-3); 121.94 (C-2); 126.59 (C-4); 127.34 (C-9); 128.28 (C-6);138.64 (C-8) (C-5 not observed). ESI-MS: 315.25 (80%), 316.47 (20%)(MH+).

The invention claimed is:
 1. A compound of formula XII

wherein n is a number from 1 to 4, R₁ is nitro, halogen, or cyano, R2 ishydrogen or unsubstituted or substituted alkyl, unsubstituted orsubstituted alkoxycarbonyl, unsubstituted or substituted arylsulfonyl,unsubstituted or substituted alkylsulfonyl, unsubstituted or substitutedaryl, carbamoyl or N-mono- or N,N-disubstituted carbamoyl, silylsubstituted by three moieties independently selected from unsubstitutedor substituted alkyl and substituted or unsubstituted aryl, or acyl, R3and R4 are, independently of each other, C₁-C₄ alkyl unsubstituted orsubstituted by alkyl, hydroxy, mercapto, nitro, cyano, halo, halo-loweralkyl, C₆-C₁₆-aryl, C₃-C₁₀-cycloalkyl, lower alkoxy, aryl-lower alkoxy,lower alkanoyloxy, N,N-di-lower alkylamino, N-phenyl-lower alkylamino,N,N-bis(phenyl-lower alkyl)-amino, di-lower alkylamino, unsubstituted orlower alkyl substituted and/or mono- or di-oxosubstitutedheterocyclylenyl or heterocyclyl, wherein C₆-C₁₆-aryl is unsubstitutedor substituted by one or more moieties selected from N,N-di-loweralkylamino, N-phenyl-lower alkyl-amino, N,N-bis(phenyl-loweralkyl)-amino, and halo-lower alkyl, or R3 and R4 together form anunsubstituted alkylene bridge (thus forming a ring with the bindingnitrogen) or an alkylene bridge to which a phenyl or a C₃-C₈-cycloalkylring is condensed at two vicinal carbon atoms of the alkylene bridge,and provided that R₁ is not 5-methoxy if n is
 1. 2. A compound offormula III*

wherein n is a number from 0 to 4, R1 is unsubstituted or substitutedalkyl, unsubstituted or substituted aryl, unsubstituted or substitutedheterocyclyl, alkylsulfonyl, sulfonyl alkyl, N-mono- orN,N-disubstituted or unsubstituted aminosulfonyl alkyl, hydroxy,mercapto, nitro, halogen, cyano, carboxamido, N-mono- orN,N-disubstituted carboxamido, carboxhydrazido, unsubstituted orsubstituted alkoxycarbonyl, unsubstituted or substituted alkoxy, formylor other alkanoyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,alkanoyloxy, N-mono- or N,N-disubstituted or unsubstituted amino,unsubstituted or substituted hydrazino, or is a residue of a boronicacid or an ester thereof, R2 is hydrogen, and HPyr⁺ is the cationresulting from a pyridine.